Challenges with Type 2 Diabetes
Prof. Samir George
Professor of Diabetes
& Endocrinology,
JAN-2009-WS-4046-ST
Cairo University
DPP4 Inhibitors
Mode of Action
Sitagliptin Enhances Active Incretin Levels
Through Inhibition of DPP-41–4
Glucose-dependent
Ingestion
of food
Pancreas
Release of
active incretins
GLP-1 and GIPa
GI tract
Sitagliptin
(DPP-4
inhibitor)
X
Inactive
GLP-1
DPP-4
enzyme
Inactive
GIP
 Insulin from
beta cells
(GLP-1 and GIP)
Beta cells
Alpha cells
 Peripheral
glucose
uptake
 Blood glucose in
fasting and
postprandial states
Glucose-dependent
 Glucagon
from alpha cells
(GLP-1)
 Hepatic
glucose
production
By increasing and prolonging active incretin levels, sitagliptin increases insulin release
and decreases glucagon levels in the circulation in a glucose-dependent manner.
DPP-4=dipeptidyl peptidase 4; GI=gastrointestinal; GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1.
aIncretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels increase in response to a meal.
1. Kieffer TJ et al. Endocr Rev. 1999;20(6):876–913.
2. Ahrén B. Curr Diab Rep. 2003;3(5):365–372.
3. Drucker DJ. Diabetes Care. 2003;26(10):2929–2940,
4. Holst JJ. Diabetes Metab Res Rev. 2002;18(6):430–441.
DPP-4 Activity is Inhibited by 97% Over
24 Hours With Sitagliptin 100 mga
Single-dose study in healthy subjects (n=6)
Sitagliptin 100 mg qd
DPP-4 Inhibition, %b
100
80
60
40
20
0
0 1 2
4
6
8
12
16
Hours Postdose
24
qd=daily.
a97% weighted average inhibition of plasma DPP-4 activity through 24 hours postdose.
bCorrected for dilutional and assay effects from baseline vs time.
Alba M et al. Curr Med Res Opin. 2009;25(10):2507–2514. eAppendix. doi: 10.1185/03007990902109514. Permission requested.
Beta-Cell Pathways to Insulin Secretion
Sulphonylurea Receptor
Potassium channel
Glucose
K+
Glucose
metabolism
GLUT2
ATP
1
Insulin
Calcium channel
[Ca2+]
2
Triggering
ATP = adenosine triphosphate; GLUT2 = glucose transporters; SUR = sulfonylurea receptor.
1. Hinke SA et al. J Physiol. 2004;558(Pt 2):369–380; 2. Henquin JC. Diabetes. 2000;49(11):1751–1760; 3. Henquin JC. Diabetes. 2004;53(suppl 3):S48–S58.
Glucose
(mmol/L)
Effects of GLP-1 on Insulin and Glucagon
Shown to Be Glucose Dependent in Type 2 Diabetes
Placebo
GLP-1 infusion
15.0
12.5
10.0
7.5
5.0
*
*
*
*
*
*
*
Glucagon
(pmol/L)
Insulin
(pmol/L)
Infusion
250
200
150
100
50
*
*
*
*
With hyperglycemia
GLP-1 stimulated insulin
and suppressed glucagon.
*
*
*
*
20
15
10
5
*
0
*
60
*
120
*
180
When glucose levels
approached normal,
insulin levels declined
and glucagon was no
longer suppressed.
240
Time (minutes)
N=10 patients with type 2 diabetes. Patients were studied on two occasions. A regular meal and drug
schedule was allowed for one day between the experiments with GLP-1 and placebo.
*p<0.05 GLP-1 vs. placebo
Adapted from Nauck MA et al Diabetologia 1993;36:741–744.
Effects of Sitagliptin and Metformin on Incretin Hormone
Concentrations in Healthy Adult Subjects:
Summary of Study Results
Total
GLP-1
Active GLP-1
Active GIP
 Increases active GLP-1 and GIP
Sitagliptin
Metformin
Sitagliptin
+
Metformin
Observations in Healthy Subjects
No
effect
 Increases total GLP-1 and increases
active GLP-1
 Does not increase active GIP
 Additive effect on active GLP-1;
increases active GIP
It is unclear what these findings mean for changes in glycemic control in patients with type 2 diabetes.
GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1.
Data available on request from Merck. Please specify 20752937(2)-JMT.
Sitagliptin and Metformin Target the Core
Metabolic Defects of Type 2 Diabetes
Sitagliptin improves
beta-cell function
and increases insulin
synthesis and
release.1
Beta-Cell
Dysfunction
Sitagliptin reduces HGO through
suppression of glucagon from alpha
cells.2
Insulin
Resistance
Metformin has insulinsensitizing properties.3–5
(Liver > Muscle, fat)
Metformin decreases HGO by
targeting the liver to decrease
gluconeogenesis and
Hepatic Glucose
Overproduction (HGO) glycogenolysis.4
1. Aschner P et al. Diabetes Care. 2006;29(12):2632–2637.
2. Data on file.
3. Abbasi F et al. Diabetes Care. 1998;21(8):1301–1305.
4. Kirpichnikov D et al. Ann Intern Med. 2002;137(1):25–33.
5. Zhou G et al. J Clin Invest. 2001;108(8):1167–1174.
Mechanisms of Action of Major Oral Monotherapies Are
Unable to Address the 3 Core Defects in Type 2 Diabetes
Mechanisms of Action
Oral Monotherapies
Improves insulin
secretion
SUs
Meglitinides


TZDs
Metformin
α-Glucosidase
Inhibitors
DPP-4
Inhibitors

Improves insulin
resistance


Lowers hepatic
glucose production



SUs=sulfonylureas; TZD=thiazolidinediones; DPP-4=dipeptidyl peptidase 4.
Inzucchi SE. JAMA 2002;287:360–372; Gallwitz B. Minerva Endocrinol. 2006;31:133–147; Nathan DM et al. Diabetologia. 2006;49:1711–1721.
Initial Fixed-Dose Combination Therapy With Sitagliptin +
Metformin vs Metformin Monotherapy: Study Design
T2DM, aged
18–78 yrs,
Off OHA
≥4 months,
HbA1c ≥7.5%
Sitagliptin 50 mg bid + metformin 1000 bida (n=626)
R
Metformin 1000 mg bida (n=624)
Screening
period
Phase A
Phase B
1 week
18 weeks
26 weeks
Screening
aMetformin
Day 1
Randomization
Week 18
Week 44
was initiated at 500 mg bid and titrated up to 1000 mg bid over 4 weeks. Patients who were unable to tolerate the
maximum dose of sitagliptin/metformin FDC or metformin were allowed to be down-titrated to a minimum dose of
sitagliptin/metformin FDC 50/500 mg bid or metformin 500 mg bid.
bid=twice daily; FDC=fixed-dose combination; OHA=oral antihyperglycemic agent; qd=once daily; R=randomization; T2DM=type 2
diabetes mellitus.
1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.
2. Data on file, MSD.
Initial Fixed-Dose Combination Therapy With Sitagliptin +
Metformin vs Metformin Monotherapy: HbA1c Results Over
18 Weeks
FAS Population
HbA1c LS Mean (±SE)
Change From Baseline, %
10
9
8
LS means
difference
–0.6; P<0.001
7
0
6
Week
12
Sitagliptin/metformin FDC (n=560)
Mean baseline HbA1c=9.9%
18
Metformin (n=566)
Mean baseline HbA1c=9.8%
FAS=full analysis set; FDC=fixed-dose combination; LS=least-squares; SE=standard error.
1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.
2. Data on file, MSD.
Initial Fixed-Dose Combination Therapy With Sitagliptin + Metformin vs
Metformin Monotherapy: Change from Baseline in HbA1c by Baseline
HbA1c at Week 18
FAS (Week 18)
Baseline HbA1c,%
Mean HbA1c,%
HbA1c LS Mean Change
from Baseline, %
0
<8
7.6
n= 87 101
≥8 and <9
8.4
124 109
≥9 and <10
9.5 9.4
99
95
≥10 and <11
10.4
99
111
≥11
12.2
150 148
–0.5
–0.8
–1.0
–1.1
–1.1
–1.5
–2.0
P=0.158
–1.6
P=0.009
–2.5
–1.7
–2.0
–2.1
P=0.111
–3.0
–3.5
–4.0
–2.7
–2.9
Sitagliptin/metformin FDC
Metformin
P<0.001
–3.6
P<0.001
FAS=full analysis set; FDC=fixed-dose combination.
1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.
2. Data on file, MSD.
Initial Fixed-Dose Combination Therapy With JANUMET™ vs
Metformin Monotherapy: Markers of Beta-Cell Function at
Week 18
Mean
baseline value:
0
Proinsulin-toinsulin ratio
0.556
0.518
60
n=458
-0.1
-0.15
–0.186
-0.2
-0.25
–0.238
–0.052a (P=0.002)
aBetween-groups
HOMA-β
54.6
22.8a (P=0.004)
50
-0.05
LS Mean
Change From Baseline
LS Mean
Change From Baseline
n=469
FAS Population
40
31.8
30
20
10
Mean 0
baseline value:
n=465
n=456
50.5
62.4
difference.
Sitagliptin/metformin FDC
Metformin
FAS=full analysis set; FDC=fixed-dose combination.
1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.
2. Data on file, MSD.
Initial Fixed-Dose Combination Therapy With Sitagliptin + Metformin vs
Metformin Monotherapy: Adverse Experience Summary
at 18 Weeks
APaT Population
Sitagliptin/
metformin FDC
(N=625)
n (%)
Metformin
(N=621)
n (%)
With one or more AEs
271 (43.4)
301 (48.5)
With no AEs
354 (56.6)
320 (51.5)
With drug-related AEsb
109 (17.4)
116 (18.7)
With serious AEs
13 (2.1)
20 (3.2)
With serious drug-related AEsb
1 (0.2)
1 (0.2)
Who died
1 (0.2)
1 (0.2)
Discontinued due to AEs
25 (4.0)
25 (4.0)
Discontinued due to drug-related AEsb
18 (2.9)
16 (2.6)
Discontinued due to serious AEs
6 (1.0)
5 (0.8)
Discontinued due to serious drug-related AEsb
1 (0.2)
1 (0.2)
Clinical AEsa
aExcluding
data after initiation of an additional antihyperglycemic agent.
by the investigator to be possibly, probably, or definitely drug-related.
AE=adverse experience; APaT=all patients as treated; FDC=fixed-dose combination.
1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.
2. Data on file, MSD.
bConsidered
Glipizide-Controlled Sitagliptin Add-on to
Metformin Noninferiority Study: Design


Patients with type 2 diabetes (on any monotherapy or dual combination with metformin)
Noninferiority design
Continue/start
metformin
monotherapy
Week -2: Eligible if A1C
6.5% to 10%
Mean baseline HbA1c:
7.65%
Glipizide: 5 mg qd increased to 10 mg bid
(held if premeal fingerstick glucose <6.1 mmol/L or hypoglycemia)
Day 1
Randomization
Screening
period
Metformin monotherapy runin period
Week 52
Double-blind treatment period:
glipizide or sitagliptin 100 mg qd
Single-blind
placebo
Metformin (stable dose >1,500 mg/day)
Glipizide dosing
 Mean titrated dose 10 mg/day
 Per protocol, glipizide was kept constant except for down-titration if needed to prevent hypoglycemia
bid=twice a day; qd=once a day.
Nauck MA et al. Diabetes Obes Metab. 2007;9(2):194–205.
HbA1c With Sitagliptin or Glipizide as Add-on
Combination With Metformin: Comparable Efficacy
Per-protocol Population
LSM change from baseline
at 52 weeks (for both groups): –0.7%
8.2
8.0
Sulfonylureaa + metformin (n=411)
7.8
Sitagliptinb + metformin (n=382)
HbA1c, % ±SE
7.6
Achieved primary
hypothesis of
noninferiority to
sulfonylurea
7.4
7.2
7.0
6.8
6.6
6.4
6.2
0
6
12
18
24
30
38
46
52
Weeks
Adapted from Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study
024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin,
compared with the sulfonylurea, glipizide, in patients with type 2 diabetes
inadequately controlled on metformin alone: a randomized, double-blind, noninferiority trial. Diabetes Obes Metab. 2007;9:194–205 with permission from
Blackwell Publishing Ltd., Boston, MA.
bSitagliptin
aSpecifically glipizide ≤20 mg/day;
100 mg/day with metformin (≥1500 mg/day).
LSM=least squares mean.
SE=standard error.
Sitagliptin With Metformin Provided Weight Reduction
(vs Weight Gain) and a Much Lower Incidence of Hypoglycemia
All-patients-as-treated Population
Least squares mean change from baseline
3
Sulfonylureaa + metformin (n=416)
Sulfonylureaa + metformin (n=584)
Sitagliptinb + metformin (n=389)
Sitagliptinb + metformin (n=588)
2
1
 between groups
at Week 52 = –2.5 kg
P<0.001
−1
−2
−3
Patients With ≥1 Episode
Over 52 Weeks, %
Body Weight, kg ± SE
50
0
Hypoglycemia
40
32%
P<0.001
30
20
10
5%
0
0
12
24
38
52
Weeks
Adapted from Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study
024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor,
sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2
diabetes inadequately controlled on metformin alone: a randomized, doubleblind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194–205 with
permission from Blackwell Publishing Ltd., Boston, MA.
Week 52
aSpecifically glipizide ≤20 mg/day;
(100 mg/day) with metformin (≥1500 mg/day);
Least squares mean between-group difference at week 52 (95% CI):
change in body weight at Week 52 = –2.5 kg [–3.1, –2.0] (P<.001);
Least squares mean change from baseline at week 52:
glipizide: +1.1 kg; sitagliptin: –1.5 kg (P<.001).
Add-on sitagliptin with metformin vs sulfonylurea
with metformin study.
bSitagliptin
Sitagliptin or Glipizide as Add-on Combination With Metformin
Post Hoc Analysis
Patients Achieving Composite EP of The composite endpoint of A1C reduction
(>0.5%), no body weight gain and no hypoglycemia Over 52 Weeks
Adapted from Thomas L. Seck et al. poster presented
American Diabetes Association 70th Scientific Sessions.
Orlando, USA. June 25–29, 2010.
Two Years extension Data
HbA1c With Sitagliptin or Glipizide as Add-on Combination With Metformin:
Comparable Efficacy
HbA1C
FPG
Adapted from T. Secket al. Int J Clin Pract, April 2010, 64, 5, 562–576.
Two Years extension Data- 2010
Sitagliptin With Metformin Provided Weight Reduction (vs Weight Gain) and Much
Lower Incidence of Hypoglycemia
Adapted from T. Secket al. Int J Clin Pract, April 2010, 64, 5, 562–576.
Efficacy, Hypoglycemia, Body Weight
 Nauck et al. 2007
Non-inferiority of sitagliptin to glipizide (on top of metformin)
 R. Arechavaleta et al. 2011
Non-inferiority of sitagliptin to glimepiride(on top of
metformin)
Published Online in Nov. 2010
Addition of Sitagliptin or Glimepiride in Patients
Inadequately Controlled on Metformin:
Study Design1
Patients ≥18 years of
age with T2DM on
stable dose of
metformin (≥1500
mg/day) for
≥12 weeks and HbA1c
6.5%– 9.0%
Sitagliptin 100 mg qd
R
Glimepiride
(started at 1 mg qd and up-titrated until week
18 as needed up to maximum dose of 6 mg qd)
Continue stable dose of metformin
Screening
Period
Week –4
Single-blind
Placebo Run-in
Week –2
Day 1
qd=once daily; R=randomization; T2DM=type 2 diabetes mellitus.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.
Double-blind
Treatment Period
Week 30
HbA1c-Lowering Efficacy of Sitagliptin at
Week 30 Was Noninferior to That of Glimepiride in
Patients Inadequately Controlled on Metformin1
Per-Protocol Population
LS Mean (±SE) HbA1c, %
8.0
Sitagliptin 100 mg + metformin (n=443)
7.8
Glimepiridea + metformin (n=436)
7.6
7.4
–0.47
7.2
7.0
–0.54
6.8
6.6
Prespecified
noninferiority
margin =
0.40%
6.4
6.2
6.0
0
6
12
18
Week
LS=least squares; SE=standard error.
aMean
 (95% CI)
0.07% (–0.03, 0.16)
dose of glimepiride (following the 18-week titration period) was 2.1 mg per day.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.
24
30
Addition of Sitagliptin or Glimepiride in Patients
Inadequately Controlled on Metformin:
Proportion of Patients at HbA1c Goal at Week 301
Per-Protocol Population
Sitagliptin 100 mg + metformin (n=443)
Patients at HbA1c Goal, %
70
Glimepiridea + metformin (n=436)
59.6
60
50
40
 (95% CI)
–7.5% (–13.8, –1.1)
52.4
 (95% CI)
–6.7% (–12.3, –1.1)
27.5
30
21.2
20
10
0
<6.5%
CI=confidence interval.
aMean
dose of glimepiride (following the 18-week titration period) was 2.1 mg per day.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.
<7.0%
Addition of Sitagliptin or Glimepiride in Patients
Inadequately Controlled on Metformin: Clinical
Assessment of Hypoglycemia Over 30 Weeks1
Patients With ≥1
Hypoglycemic Episode, %
APaT Population
 (95% CI)
–15.0% (–19.3, –10.9)
(P<0.001)
25
22
Sitagliptin 100 mg
+ metformin (n=516)
Glimepiridea
+ metformin (n=518)
20
15
10
7
5
0
APaT=all patients as treated; CI=confidence interval.
aMean
dose of glimepiride (following the 18-week titration period) was 2.1 mg per day.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.
Addition of Sitagliptin or Glimepiride in Patients
Inadequately Controlled on Metformin:
Body Weight Change from Baseline1
LS Mean Change (±SE) in Body
Weight From Baseline, kg
APaT Population
Sitagliptin 100 mg + metformin
2
Glimepiridea + metformin
1.2 kgb
1
 = –2.0 kg
(P<0.001)
0
–0.8 kgb
–1
0
6
12
APaT=all patients as treated; LS=least squares; SE=standard error.
aMean
18
24
30
Week
dose of glimepiride (following the 18-week titration period) was 2.1 mg per day. bLS mean body weight change at 30 weeks.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.
Impact of Hypoglycemia
380,000 Emergency Department visits per year
in the U.S (1993 -2005) were attributed to Hypoglycemia
 5 million emergency department visitsa between 1993
and 2005 for hypoglycemia1
– 25% resulted in hospital admission
– 72% of patients had hypoglycemia as the primary
(first-listed) diagnosis
– ~44% of reported cases occurred in adults
≥65 years of age
1. Ginde AA et al. Diabetes Care. 2008;31:511–513.
2. Matyka K et al. Diabetes Care. 1997;20(2):135–141.
Vicious circle of hypoglycemia awareness
Frequent hypoglycemias
<60 mg/dl
Hypoglycemic
events
lead
hypoglycaemic
events
Awareness of hypoglycemia:
- more difficult
- less reliable
Adapted from Hermanns et al. Diabetologie 2009; 4: R 93-R112
Symptoms of hypoglycemia:
- weaker
- appear later
- change
Asymptomatic Episodes of Hypoglycemia May
Go Unreported
100
Patients, %
75
55.7
62.5
46.6
50
25
0
n=70
n=40
n=30
All patients
with diabetes
Type 1
diabetes
Type 2
diabetes
 In a cohort of patients with
diabetes, more than 50% had
asymptomatic (unrecognized)
hypoglycemia, as identified by
continuous glucose
monitoring1
 Other researchers have
reported similar findings2,3
Patients With ≥1 Unrecognized
Hypoglycemic Event, %
1. Copyright © 2003 American Diabetes Association. Chico A et al. Diabetes Care. 2003;26(4):1153–1157.
Reprinted with permission from the American Diabetes Association.
2. Weber KK et al. Exp Clin Endocrinol Diabetes. 2007;115(8):491–494.
3. Zick R et al. Diab Technol Ther. 2007;9(6):483–492.
Complications and Effects of Severe
Hypoglycemia
Plasma glucose level
6
110
100
5 90
80
4
70
60
3
50
40
2
30
1 20
mmol/L
10
mg/dL
1. Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307.
2. Cryer PE. J Clin Invest. 2007;117(4):868–870.
Increased Risk of Cardiac
Arrhythmia1
 Abnormal prolonged cardiac
repolarization—
↑ QTc and QTd
 Sudden death
Progressive
Neuroglycopenia2
 Cognitive impairment
 Unusual behavior
 Seizure
 Coma
 Brain death
Severe Hypoglycemia Causes QTc Prolongation
P=0.0003
450
Mean QT interval, ms
440
430
420
P=NS
410
400
390
380
Significant QTc prolongation
during
hypoglycemia
370
360
0
Euglycemic clamp
(n=8)
Baseline (t=0)
Hypoglycemic clamp
2 weeks after
glibenclamide withdrawal
(n=13)
End of clamp (t=150 min)
Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307.
ACCORD?
Characteristics of Patients at an Increased Risk of
Hypoglycemia
Insulin/
Insulin
secretagouge
Impaired
awareness
Advanced
age
Hypoglycemia
Missed/
irregular
meals
1. Henderson JN et al. Diabet Med. 2003;20:1016–1021.
2. Miller CD et al. Arch Intern Med. 2001;161:1653–1659.
Long duration
of diabetes
Hypoglycemia May Be a Barrier to Glycemic Control in
Patients With Type 2 Diabetes
 Hypoglycemia is an important limiting factor in glycemic management and
may be a significant barrier to treatment adherence.
 Fear of hypoglycemia is an additional barrier to control.
– A study in patients with type 2 diabetes showed
increased fear of hypoglycemia as the number of
mild/moderate and severe hypoglycemic events
increased.
Amiel SA et al. Diabet Med. 2008;25(3):245–254.
Guidelines: HbA1c Goal as Close to Normal as
Possible Without Significant Hypoglycemia
 ADA 20081
…. the HbA1c goal for selected individual patients is as close to
normal (<6%) as possible without significant hypoglycemia.a
 IDF 2005
2
…….. and titrate therapies, to enable people with diabetes to achieve
HbA1c below 6.5%
Sometimes raise targets for people on insulin or sulfonylurea therapy
in whom attainment of tighter targets may increase the risk of
hypoglycemic episodes, which may present particular problems for
people with other physical or mental impairment.
……… exercise caution if hypoglycemia may be a problem to the
individual.
aFor
those with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid
conditions or long-standing diabetes in whom the general goal is difficult to attain, less stringent HbA1c goals should be considered. Specific goals for people
with these conditions should be determined by an individual’s health care team.2,3
1. ADA. Diabetes Care. 2008;31(suppl 1):S12–S54.
2. IDF 2005 Clinical Guidelines Task Force. http://www.idf.org/home/index.cfm?node=1457. Accessed December 12, 2008.
More Hypoglycemic Events Have Been Reported by
Patients Treated With a Sulfonylurea (Glyburide) vs
Metformin or a Thiazolidinedione
Patients Self-Reporting
Hypoglycemic Events, %
ADOPT (patients with new-onset diabetes)1
50
38.7a
40
30
20
9.8
11.6
10
0
1
TZD
(Rosiglitazone)
Metformin
Sulfonylurea
(Glyburide)
Other studies have also shown an increased frequency of hypoglycemic events in
patients with type 2 diabetes treated with a sulfonylurea compared with patients
treated with metformin or a TZD.2
ADOPT=A Diabetes Outcome Progression Trial; TZD=thiazolidinedione.
aP≤0.01 for the comparison between this treatment group and the rosiglitazone group.
1. Kahn SE et al. N Engl J Med. 2006;355(23):2427–2443.
2. Bolen S et al. Ann Intern Med. 2007;147(6):386-399.
Sitagliptin & Hypoglycemic events
 Most previous studies of sitagliptin as monotherapy or in combination with
metformin or a PPARγ agonist showed:
– Incidence of hypoglycemia generally similar to placebo
– Low rate of hypoglycemia observed with sitagliptin
consistent with glucose-dependent mechanism of
insulin secretion and glucagon suppression
PPARγ=peroxisome proliferator-activated receptor gamma.
T. Vilsbøll et al. Diabetes, Obesity and Metabolism 12: 167–177, 2010.
2011
HYPOGLYCEMIA SURVEY
39
Survey objective and methodology


Conducted to gain insights into communication between healthcare professionals and patients with type 2 diabetes about hypoglycemia and
to determine awareness and understanding of the condition in six countries:
–
Brazil
–
Turkey
–
China
–
Mexico
–
Saudi Arabia
–
India
Total of 950 patients (aged 18-75) and 425 physicians were interviewed via a mix of telephone, face-to-face and direct online interviews
– 53% endocrinologists, 12% General Practitioner / family physician, 16% specialist
in internal medicine, 3% cardiologists and 16% diabetes specialists /
diabetologists
– 56% of respondents were male and 44% were female

The questionnaire took approximately 20 minutes to complete

The data was primarily collected between March and May 2011
40
Some patients mistakenly link symptoms of
hyperglycemia with hypoglycemia
The majority of patients
recognize the key symptoms of
hypoglycemia
However some patients mistakenly
linked thirst and frequent urination
(symptoms of hyperglycemia) to
hypoglycemia
59
60
50
40
% patients 30
20
38
40
37
28
22
18
10
6
0
Q1. Which of the following are symptoms of hypoglycemia (low blood sugar?) Base: all patients
41
Nearly three quarters of patients were unaware that
hypoglycemia can be caused by certain diabetes medications
Over a tenth of patients do not know
the causes of hypoglycemia
45
In India, 86% of
patients were
unaware that
hypoglycemia can be
caused by certain
diabetes medications
43
39
40
35
30
% patients
25
29
28
21
20
11
15
10
7
5
0
Q2. Hypoglycemia (low blood sugar) can be caused by…? Base: all patients
42
45% of patients have previously needed assistance from
others as a result of having hypoglycemia and 44% have
received emergency medical care
% patients who have previously needed assistance from others
No
55 55
Yes
In Saudi Arabia, over
three quarters of
patients have received
emergency medical
care and nearly two
thirds needed
assistance from others
as a result of having
hypoglycemia
45
45
Yes
No
No
Yes
56
56
44
44
Yes
No
% patients who have received emergency medical care
Q8. Have you ever experienced emergency medical care as a result of having hypoglycemia (low blood sugar)? Base: all patients
Q9. Have you ever needed assistance from others as a result of having hypoglycemia (low blood sugar)? Base: all patients
43
Fainting, seizure and loss of consciousness are
the three most important patient concerns
associated with hypoglycemia
45
43
41
39
40
35
30
25
% patients
19
17
20
15
12
14
15
10
5
0
Q10 What are your biggest concerns relating to your type 2 diabetes? Base: all patients
44
Hypoglycemia can impact daily activities
35
Working
14
Travelling
16
Exercising
12
Driving
I have never experienced hypoglycaemia during any of these
activities
44
0
5
10
15
20
25
30
35
40
45
% patients
Over a third of patients have
experienced hypoglycemia at
work and 16% have experienced
hypoglycemia whilst exercising
Q6. Have you ever experienced hypoglycemia (low blood sugar) during the following activities? Base: all patients
45
Over half of physicians would change medication as the
first course of action when a patient presents with
hypoglycemia
Total
(425)
Brazil
(75)
China
(75)
India
(75)
Mexico
(75)
Saudi
(75)
Turkey
(50)
46
Ramadan Study
The incidence of hypoglycaemia in Muslim patients with type 2
diabetes treated with sitagliptin or a sulphonylurea during Ramadan:
a randomized trial
Background
 78.8% of patients with type 2 diabetes fast during Ramadan, with a 7.5-fold increase in
the incidence of severe hypoglycaemia.
 There is no consensus about the most appropriate oral antihyperglycaemic agent(s) for
patients with type 2 diabetes to use during Ramadan.
 SU is typically recommended in combination with metformin because of broad clinical
experience and lower cost. The ADA recommends caution when using SU during
Ramadan because they are associated with an increased risk of hypoglycaemia.
 Sitagliptin when added to ongoing metformin monotherapy was shown to reduce the
incidence of symptomatic hypoglycaemia 3- to 6-fold compared with the addition of a
SU in patients with type 2 diabetes.
 Given the low risk of hypoglycaemia demonstrated in previous sitagliptin trials in nonfasting patients with type 2 diabetes, it was of interest to evaluate the incidence of
hypoglycaemia with sitagliptin during Ramadan fasting.
Salti I, Benard E, Detournay B et al. A population-based study of diabetes and its characteristics during the fasting month of Ramadan in 13 countries: results of the epidemiology of diabetes and Ramadan
1422/2001 (EPIDIAR) study. Diabetes Care 2004; 27: 2306-11.
Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 2002; 287: 360-72.
Malik S, Lopez V, Chen R, Wu W, Wong ND. Undertreatment of cardiovascular risk factors among persons with diabetes in the United States. Diabetes Res Clin Pract 2007; 77: 126-33.
Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes
inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2007; 9: 194-205.
Arechavaleta R, Seck T, Chen Y et al. Efficacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, doubleblind, non-inferiority trial. Diabetes Obes Metab 2011; 13: 160-8.
Data on file, MSD
Aim
 To compare the incidence of symptomatic hypoglycaemia in fasting
Muslim patients with type 2 diabetes treated with sitagliptin or a SU
during Ramadan.
Data on file, MSD
Study Design
1066 patients
≥ 18 yrs
HbA1c <10%
Fasting during Ramadan
Screen patient
according to
inclusion and
exclusion
criteria
SU stable-doseSU (glimepiride,
gliclazide or glibenclamide [glyburide]
Sitagliptin 100 mg/day
± Metformin
R
± Metformin
Continue stable dose SU
± Metformin
Mean age: 55 yrs
Mean HbA1c: 7.5%
Mean disease duration: 5-6 yrs
4 weeks
wk 1
Start of
Ramadan
Data on file, MSD
wk 2
wk 3
wk 4
1ry E.P: overall incidence of
symptomatic hypoglycaemia recorded
during Ramadan
Method [cont’d]

The study proceeded under real-life conditions & patients completed daily diary cards to document
information on hypoglycaemic symptoms and complications.
– Physicians were able to change drug and/or dose if needed to optimally
manage their patients.
 Ramadan 2010
 43 sites in 6 countries including Egypt
 Egypt sites :
–
National Diabetes institute
–
Ain Shams University
–
Nasser Institute
–
Alexandria University
Data on file, MSD
Results
 1ry E.P.: the proportion of patients who recorded ≥1 symptomatic
hypoglycaemic events during Ramadan was 4.8% in the sitagliptin group
and 14.3% in the SU group.
 The proportion of patients with hypoglycaemic events (symptomatic or
asymptomatic) was 8.5% in the sitagliptin group and 17.9% in the SU
group
 The risk of hypoglycaemia (symptomatic or asymptomatic) was
significantly decreased with sitagliptin relative to SU treatment.
 The risk of symptomatic hypoglycaemia was decreased by 67% with
sitagliptin relative to SU treatment.
% patients experiencing symptomatic
hypoglycaemia
Egypt
Data on file, MSD
Sitagliptin
SU
0%
18.6%
Conclusion
 In Muslim patients with type 2 diabetes who observed the fast during
Ramadan, switching to a sitagliptin-based regimen decreased the
incidence of hypoglycaemia compared to remaining on a SU-based
regimen.
Data on file, MSD
Impact of Weight gain
SU and weight gain (UPKPS 34)
8
Insulin
Change in weight (kg)
7
6
5
SU
4
3
2
Conv.
Met
1
0
0
3
6
9
12
Years from randomisation
Conventional treatment (n=411)*
Insulin (n=409)
Glibenclamide (n=277)
Metformin (n=342)
*diet initially then sulphonylureas, insulin and/or metformin if FPG >15 mmol/l
UKPDS 34. Lancet 1998:352:854–865. n=at baseline;
55
Abdominal obesity is linked to a higher risk for
myocardial infarction
INTERHEART-Study:
Case control study in 52 countries: 15152 cases vs 14820 controls
Abdominal obesity* leads to a significantly higher risk
for myocardial infarction:
OR (99%CI): 4.5 and 4.7 in W Eur and N Amer population
*waist/hip/ratio: upper tertile vs lowest tertile
Yusuf S. et al. Lancet 2004; 364:937-52
Beta-cell function
UKPDS: progressive decline of
-cell function over time
-cell function (%)
100
Start of treatment
80
60
40
20
P < 0.0001
0
–10 –9 –8 –7 –6 –5 –4 –3 –2 –1
1
2
3
4
5
6
Time from diagnosis (years)
HOMA model, diet-treated
n = 376
Adapted from Holman RR. Diabetes Res Clin Pract 1998; 40 (Suppl.):S21–S25.
Sitagliptin Lowered and Glipizide Increased
the Proinsulin-to-Insulin Ratio
Sitagliptin 100 mg
0.05
LS mean change
from baseline ± SE
Glipizide
0.03
0.01
-0.01
-0.03
-0.05
0
24
Week
Per protocol population.
Nauck MA et al. Diabetes Obes Metab 2007;9:194–205.
52
Per protocol population.
Nauck MA et al. Diabetes Obes Metab 2007;9:194–205.
Efficacy and Safety of JANUVIA™† (sitagliptin, MSD) When Added to
Insulin Therapy in Patients with Type 2 Diabetes (Alone or in Combination
With Metformin)
Protocol Number 051
T. Vilsbøll et al. Diabetes, Obesity and Metabolism 12: 167–177, 2010.
Addition of Sitagliptin to Insulin Therapy:
Study Design
• Patients with type 2 diabetes
• Age >21 years
24-Week Stable Insulin Dose Period
• Receiving insulin (including
glargine, detemir, ultralente, NPH,
lente, or premixed insulin) alone
or with metformin ≥1500 mg/day
• Not receiving premeal shortacting insulin
Sitagliptin 100 mg QD (n=322)
• HbA1c ≥7.5% and ≤11%
R
• Continue on a stable dose of
insulin with or without metformin
Placebo (n=319)
• Begin single-blind run-in period
Single-blind
placebo run-in
period
Screening
visit
Week –2
Randomization
QD=daily.
T. Vilsbøll et al. Diabetes, Obesity and Metabolism 12: 167–177, 2010.
Week 24
Addition of Sitagliptin to Insulin Therapy:
HbA1c Change From Baseline Over Time
FAS Population (LOCF)
HbA1c LS Mean Change
From Baseline, % (SE)
0.1
0.0
–0.03%
–0.1
(n=312)
–0.2
Difference = –0.56%
(P<0.001)
–0.3
–0.4
–0.5
–0.59%
–0.6
–0.7
(n=305)
–0.8
0
aBaseline
6
12
Weeks
18
24
mean HbA1c: 8.72% for sitagliptin, 8.64% for placebo
FAS=full analysis set; LOCF=last observation carried forward; LS=least squares; SE=standard error.
T. Vilsbøll et al. Diabetes, Obesity and Metabolism 12: 167–177, 2010.
Sitagliptina
Placeboa
Addition of Sitagliptin to Insulin Therapy: HbA1c
Change From Baseline by Insulin Type
FAS Population at 24 Weeks (LOCF)a
Receiving
Premixed
Insulin
Mean baseline HbA1c, %
HbA1c LS Mean Change
From Baseline, % (SE)
0.0
8.50
n=80
–0.2
n=80
8.76
8.69
n=225
n=232
–0.04
–0.02
Sitagliptin
–0.4
Placebo
–0.6
–0.8
–1.0
aExcluding
8.59
Receiving Long- or
Intermediate-acting
Insulin
P-value for treatment by
subgroup interaction = 0.949
–0.58
P<0.001
–0.61
P<0.001
data after initiation of rescue therapy.
FAS=full analysis set; LOCF=last observation carried forward; LS=least squares; SE=standard error.
T. Vilsbøll et al. Diabetes, Obesity and Metabolism 12: 167–177, 2010.
Addition of Sitagliptin to Insulin Therapy: HbA1c
Change From Baseline by Metformin Use
FAS Population at 24 Weeks (LOCF)a
Not Receiving
Metformin
Mean baseline HbA1c, %
8.68
HbA1c LS Mean Change
From Baseline, % (SE)
0.4
8.73
8.60
n=223
n=229
0.10
0.2
0.0
n=82
n=83
Sitagliptin
N=223 N=229
Placebo
–0.2
–0.13
–0.4
P-value for treatment
by subgroup
interaction = 0.437
–0.6
–0.8
–1.0
aExcluding
8.76
Receiving
Metformin
–0.55
P<0.001
–0.66
P<0.001
data after initiation of rescue therapy.
FAS=full analysis set; LOCF=last observation carried forward; LS=least squares; SE=standard error.
T. Vilsbøll et al. Diabetes, Obesity and Metabolism 12: 167–177, 2010.
Addition of Sitagliptin to Insulin Therapy:
Proportion of Patients at HbA1c Goal
FAS Population at 24 Weeks (LOCF)a
P<0.001
Patients at HbA1c Goal, %
15
Sitagliptin (n=305)
12.8
Placebo (n=312)
10
P=0.584
5.1
5
2.3
1.9
0
<7.0%
<6.5%
HbA1c Goal
aExcluding
data after initiation of rescue therapy.
FAS=full analysis set; LOCF=last observation carried forward.
T. Vilsbøll et al. Diabetes, Obesity and Metabolism 12: 167–177, 2010.
Guidelines and Consensus
Statements
for the treatment of
Type 2 Diabetes
Guideline Flowchart Overview
 AACE/ACE Consensus statement
 Canadian Guidelines
 NICE Guidelines
Glycemic Control Algorithm, Endocr Pract. 2009;15(No. 6 540-559)
2008 CDA Pharmacotherapy Algorithm
L
I
F
E
S
T
Y
L
Clinical assessment
Lifestyle intervention (initiation of nutrition therapy and physical activity)
A1C < 9.0%
Initiate
metformin
A1C ≥ 9.0%
Initiate pharmacotherapy immediately without waiting
for effect from lifestyle interventions:
• Consider initiating metformin
concurrently with another agent
from a different class; or
Symptomatic hyperglycemia with
metabolic decompensation
Initiate
insulin ±
metformin
• Initiate insulin
If not at target
Add an agent best suited to the individual:
• Alpha-glucosidase inhibitor
• Incretin agent: DPP-4 inhibitor
• Insulin
• Insulin secretagogue: meglitinide, sulfonylurea
• TZD
• Weight-loss agent
E
Timely adjustments to and/or addition of antihyperglycemic agents should be made to attain target A1C within 6-12 months
CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes 2008; 32(suppl 1):S1-S201.
NICE Algorithm1,2
HbA1C ≥ 6.5%* after trial of lifestyle measures
Metformin
Consider SU in people who
• Are not overweight
• Require a rapid response due to hyperglycaemic symptoms
• Are unable to tolerate metformin or where metformin is contra-indicated
HbA1C ≥ 6.5%*
Usual approach
Alternatives
SU
DPP-4 inhibitor
Where blood glucose
control remains or becomes
inadequate on metformin
Consider adding instead of an SU where
• Patients are at significant risk of
hypoglycaemia or its consequences
• Patients are intolerant of or contra-indicated
to SU
May be preferable to TZD where
• Further weight gain would cause or
exacerbate significant problems associated
with a high body weight
• TZDs are contra-indicated
• Previous poor response or intolerance to a
TZD
Where either a DPP-4 inhibitor or a TZD
may be suitable, the choice of treatment
should be based on patient preference
TZD (glitazones)†
Consider adding instead of an SU where
• Patients are at significant risk of
hypoglycaemia
or its consequences
• Patients are intolerant of or contra-indicated
to SU
May be preferable to DPP-4 inhibitors
where
• The patient has marked insulin insensitivity
• DPP-4 inhibitors are contra-indicated
• Previous poor response or intolerance to a
DPP-4 inhibitor
Where either a DPP-4 inhibitor or a TZD
may be suitable, the choice of treatment
should be based on patient preference
Adapted from references 1 and 2
* Or individually agreed target. Monitor patient following initiation of a new therapy and continue only if beneficial metabolic response occurs (refer to guideline for suggested
metabolic responses). Discuss potential risks and benefits of treatments with patients so informed decision can be made.
† When selecting a TZD take into account up-to-date advice from the relevant regulatory bodies, cost, safety and prescribing issues. Do not commence or continue a TZD in
people who have heart failure, or who are at higher risk of fracture.
DPP-4 Inhibitors Positioning
Guideline
DPP-4 inhibitors
AACE/ACE
1st line as monotherapy or combination
Canadian
2nd line as combination
[after Metformin]
NICE
2nd line as combination
[after Metformin &/or SU]
Mean ± SE Change in HbA1c,
%
Add-on to Metformin if MET
monotherapy Fails
The
earlier
the
better
Add-on to SU or SU+ MET if
monotherapy or dual therapy Fails
8.8
9.0
8.4
8.0
A1C (%)
8.5
7.6
7.2
8.0
0
0
6
12
18c
Week
Sitagliptina + metforminb (n=95)
24
6
12
Weeks
30
18
24
Sitagliptin +Glim + MF
Placebo + Glim + MF
Sitagliptin + Glim
Placebo + Glim
Placebo + metforminb (n=92)
NEW!!!
Add-on to INSULIN if INS
monotherapy Fails
Add-on to TZD or TZD+ metformin if
TZDs monotherapy Fails
0.1
0.1
HbA1c LS Mean Change
From Baseline, % (SE)
0.0
–0.3
–0.7
–1.1
–1.5
–0.03%
–0.1
(n=312
)
–0.2
–0.3
–0.4
–0.5
–0.6
–0.59%
–0.7
0 6 12182430 3 424854
6
(n=305)
–0.8
Sitagliptina
0
6
12
Weeks
18
24
Placeboa
THANK YOU
JAN-2009-WS-4046-ST