Transcript Prague TTT Outline – Day 2

Overview and rational of main international
guiderlines for the treatment of type 2
diabetes
Dr. med. Bernd Voss
Specialist in Internal Medicine / Munich, Germany
Regional Director Medical Affairs Diabetes
Eastern Europe, Middle East, Africa
MSD
2
Development and Progression of Type 2 Diabetes
and Related Complications1,a
Progression of Type 2 Diabetes Mellitus
Insulin resistance
Hepatic glucose
production
Insulin level
Beta-cell function
Postprandial
glucose
Fasting plasma
glucose
4–7 years
Development of Microvascular Complications
Development of Macrovascular Complications
Impaired Glucose Tolerance
Frank Diabetes
Diabetes Diagnosis
aConceptual representation.
1. Reprinted from Primary Care, 26(4), Ramlo-Halsted BA, Edelman SV, The natural history of type 2 diabetes. Implications for clinical practice, 771–789, © 1999, with permission from Elsevier.
3
UKPDS: Correlation Between HbA1c and
Macro- and Microvascular End Points1
Fatal and Nonfatal Myocardial Infarction
Microvascular End Points
5
15
Hazard Ratio
10
1
14% decrease per 1% decrement in HbA1c
P < 0.0001
0 .5
1
37% decrease per 1% decrement in HbA1c
P < 0.0001
0.5
0
5
6
7
8
9
10
11
0 5
6
7
8
9
10
Updated Mean HbA1c
UKDPS= UK Prospective Diabetes Study.
1. Reproduced from the British Medical Journal, Stratton IM, Adler AI, Neil AW, et al., Vol. 321, 405-412, copyright notice (2000) with permission from BMJ Publishing Group Ltd.
11
ADA/EASD Consensus statement 2012
Type 2 diabetes
The management of type 2 diabetes
NICE clinical guideline, May 2009
www.nice.org.uk
Developed by the National Collaborating Centre for Chronic
Conditions and the Centre for Clinical Practice at NICE
Algorithm
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
1
HbA1C ≥ 6.5%*
2+
Usual approach
SU
Where blood glucose control
remains or becomes inadequate
on metformin
Alternatives
DPP-4 inhibitor
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 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
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
3+
HbA1C ≥ 7.5%*
Insulin
Sitagliptin
TZD (glitazones)†
(NPH insulin, long-acting insulin
analogues, pre-mix insulin)
Monitor use and response and
adjust doses if necessary
Where insulin is unacceptable
or inappropriate
Where insulin is unacceptable
or inappropriate
Exenatide
If BMI ≥35 kg/m2‡ and there are problems
associated with high body weight; or BMI <35
kg/m2‡ and insulin is unacceptable because
of occupational implications or weight loss
would benefit other co-morbidities
* 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.
‡ In people of European descent (adjusted for other ethnic groups)
IDF Guidelines 2012
© International Diabetes Federation, 2012, ISBN 2-930229-43-8. This document is also available at www.idf.org
Guidelines of the German Diabetes Society DDG
Matthaei S et al. Medical Antihyperglycaemic Treatment of Diabetes …
Exp Clin Endocrinol Diabetes 2009; 117: 522 – 557
Guidelines of the German Diabetes Society DDG
(continued)
Matthaei S et al. Medical Antihyperglycaemic Treatment of Diabetes … Exp Clin Endocrinol Diabetes 2009; 117: 522 – 557
SIGN
Scottish Intercollegiate Guidelines Network
Part of NHS Quality Improvement Scotland
Management of Diabetes
March 2010
ISBM 978 1 905813599
www.sign.ac.uk
12
HbA1c Goal
≤6.5% a
HbA1c 6.5%–7.5% b
HbA1c 7.6%–9.0%
HbA1c >9.0%
Drug Naive
Symptoms
TZD e AGI f
2–3 Months
Dual Therapy
GLP-1 or DPP-4
MET
g
MET
+
MET
+
2–3 Months
GLP-1
or DPP-4 d
Colesevelam
MET
f
2–3 Months
g
+
GLP-1
or DPP-4 d
+ SU j
TZD e
2–3 Months
TZD e
+
Glinide or SU i,j
2–3 Months
+
± SU j
TZD e
GLP-1
or DPP-4 d
g
INSULIN
± Other Agent(s) k
g
a
b
c
d
e
f
g
h
i
j
k
l
m
INSULIN
± Other Agent(s) k
MET
g
+ TZDe
Triple Therapy
MET +
GLP-1 or
DPP-4 d
INSULIN
± Other
Agent(s) k
GLP-1
or DPP-4 d
INSULIN
± Other
Agent(s) k
± TZD
e
Triple Therapy m
GLP-1 or DPP-4 d
AGI
d
SU or Glinide h,i
Glinide or SU h
TZD
+
GLP-1 or DPP-4
or TZD e
d
TZD e
+
No Symptoms
Dual Therapy l
Monotherapy
MET c DPP-4 d GLP-1
Under Treatment
May not be appropriate for all patients
For patients with diabetes and HbA1c <6.5%, pharmacologic Rx
may be considered
Preferred initial agent
DPP-4 if  PPG and  FPG or GLP-1 if  PPG
TZD if metabolic syndrome and/or NAFLD
AGI if  PPG
If HbA1c goal not achieved safely
Low-dose secretagogue recommended
Glinide if  PPG or SU if  FPG
Decrease secretagogue by 50% when added to GLP-1 or DPP-4
a) Discontinue insulin secretagogue with multidose insulin
b) Can use pramlintide with prandial insulin
If HbA1c <8.5%, combination Rx with agents that cause
hypoglycemia should be used with caution
If HbA1c >8.5%, in patients on dual therapy, insulin should be
considered
AACE=American Association of Clinical Endocrinologists; ACE=American College of Endocrinology; AGI=α-glucosidase inhibitor;
DPP-4=dipeptidyl peptidase-4; FPG=fasting plasma glucose; GLP-1=glucagon-like peptide-1; MET=metformin;
NAFLD=nonalcoholic fatty liver disease; PPG=postprandial glucose; SU=sulfonylurea; TZD=thiazolidinedione.
1. Rodbard HW et al. Endocr Pract. 2009;15(6):540–559. Permission obtained from American Association of Clinical Endocrinologists.
13
DPP-4 Inhibitors in the AACE/ACE Diabetes
Algorithm For Glycemic Control1
 A guiding principle of the current algorithm is “the
recognition of the importance of avoiding hypoglycemia.”
 The AACE/ACE diabetes algorithm favors the use of DPP-4
inhibitors and GLP-1 agonists as dual therapy with
metformin over sulfonylureas, in patients with HbA1c levels
6.5%-9.0%, based on efficacy and overall safety profiles.
– Sulfonylureas have been associated with greater risks of
hypoglycemia and weight gain.
 In combination with metformin, DPP-4 inhibitors are a
preferred oral option in dual therapy for patients with HbA1c
levels between 6.5% and 9.0%.
AACE=American Association of Clinical Endocrinologists; ACE=American College of Endocrinology;
DPP-4=dipeptidyl peptidase-4; GLP-1=glucagonlike peptide-1.
1. Rodbard HW et al. Endocr Pract. 2009;15(6):540–559.
NHANES: Patients With Diabetes Are Not at Goal
(A1C <7%)1
57
43
48
n=790
NHANES=National Health and Nutrition Examination Survey.
1. Cheung BM, et al. Am J Med. 2009;122:443–453.
38
37
62
54
44
37
n=904
41
15
Persistence of Metformin Monotherapy in Patients Not at
HbA1c Goal1
Retrospective analysis using a large US electronic
medical record database (N=12,566)a
Proportions of Patients on
Metformin Monotherapy
1.00
All patients (Mean HbA1C = 8.0%)
Index HbA1C 7% to <8%
Index HbA1C 8% to <9%
Index HbA1C ≥9%
14.0 months
0.75
0.50
0.25
0.00
0
1
2
3
4
5
Years
FPG=fasting plasma glucose.
aPatients with type 2 diabetes and HbA ≥7% or ≥2 FPG levels ≥126 mg/dL while on metformin monotherapy for ≥6 months; index period of January 1, 1997 to December 31, 2008; mean
1C
follow-up time = 2.9 years
1. Fu AZ et al. Diabetes Obes Metab. 2011;13:765–769.
16
Cardiovascular Complications Are Very
Costly Among Patients With Diabetes1
US health care expenditures for chronic complications of diabetes in 2007:
hospital inpatient expenses based on annual medical claims for 16.3 million people
21000
$ US, millions
18000
15000
12000
9000
6000
3000
0
Neurologic
1. ADA. Diabetes Care. 2008;31:596–615.
Peripheral
Vascular
Cardiovascular
Renal
Metabolic
Ophthalmic
Other
17
Hypoglycemia Is Associated With
Increased Health Care Costs1
 A retrospective cohort study of inpatients with diabetes compared those who developed
laboratory evidence of hypoglycemia after 24 hours of hospitalization to those who did not
develop hypoglycemia during their entire hospital stay
Base-case analysis (blood glucose <70 mg/dL)
Patients With
Hypoglycemia
Hospital Outcomes,
mean
Patients Without
Hypoglycemia
Between-Group
Difference or Odds
Ratio (unadjusted)a
P
n
Mean
Value
n
Mean
Value
Length of hospital
stay, d
8234
11.7
95,579
5.1
6.6
<0.001
Hospital mortality, %
7994
4.8
93,012
2.3
2.12a
<0.001
Discharged to skilled
nursing facility, %b
7787
26.5
93,134
14.5
1.83a
<0.001
Total hospital charges,
2006 $
6020
85,905
72,681
54,038
59%
<0.001
aDifference is
shown as the percentage difference for charges, mean difference in days for length of stay, odds ratio for hospital mortality, and odds
ratio for discharge to SNF.
bPatients who were admitted to the hospital from a SNF were excluded from this analysis.
1. Copyright © 2009 AACE. Curkendall SM et al. Endocr Pract. 2009;15(4):302–312. Reprinted with permission from the AACE.
Potential 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;117:868–870.
Arrythmia1
 Abnormal prolonged
cardiac repolarization —
↑ QTc and QT dispersion
 Sudden death
Neuroglycopenia2





Cognitive impairment
Unusual behavior
Seizure
Coma
Brain death
18
ADVANCE: Severe Hypoglycemia Was Associated
With Adverse Clinical End Points and Death1
HR (95% CI):
3.27 (2.29–4.65)a
HR (95% CI):
3.53 (2.41–5.17)a
HR (95% CI):
2.19 (1.40–3.45)a
b
HR (95% CI):
3.79 (2.36–6.08)a
HR (95% CI):
2.80 (1.64–4.79)a
b
ADVANCE=Action in Diabetes and Vascular disease: PreterAx and DiamicroN-MR Controlled Evaluation; CI=confidence interval; CV=cardiovascular; HR=hazard ratio.
aAdjusted for multiple baseline covariates. bPrimary end points. Major macrovascular event=CV death, nonfatal myocardial infarction, or nonfatal stroke; major microvascular event=new or
worsening nephropathy or retinopathy.
1. Zoungas S et al. N Engl J Med. 2010;363:1410–1418.
19
Non-Severe Hypoglycemic Events Were
Associated With Substantial Loss of Productivity1
Estimated Productivity Loss Due to
Absenteeism From an NSHE, $a
1,404 adult patients with self-reported type 1 or type 2 diabetes participated in a 20-minute internet survey conducted in
4 countries to assess the effect of NSHEs occurring during work, outside of work hours, and overnight, on productivity.
Analysis sample consisted of all respondents who reported an NSHE in the past month.
n = 307 n = 278 n = 205
n = 287 n = 232 n = 153
n = 173 n = 170 n = 88
n = 279 n = 283 n = 166
The majority of patients were treated with insulin (72.9% with insulin vs 27.1% with oral antihyperglycemic agents).
Significant cross-country differences were found for age, gender, and diabetes duration (P<0.001 for each).
NSHE=non-severe hypoglycemic event.
aThese estimates were calculated based on the proportion of respondents reporting missed work, multiplied by hourly income and hours missed; the 2009 gross domestic product per capita
was used to estimate annual income.
1. Brod M et al. Value Health. 2011;14:665–671.
20
21
Significantly More Emergency Department Visits and
Hospital Admissions Associated With Hypoglycemia1
Hypoglycemia
Other reasons
Emergency department visits
Hospital admissions
1.2
0.9
0.8
1.0
Annual Average
Annual Average
0.7
0.6
0.5
0.4
0.3
0.2
0.6
0.4
0.2
0.1
0.0
0.0
Any hypoglycemia
aIncludes
0.8
claima
No hypoglycemia
claima
Any hypoglycemia claima
insulin-treated patients with type 1 and type 2 diabetes; US medical insurance claims.
Hypoglycemia occurrence= claims coded by (ICD-9-CM) 250.8, 251.1, or 251.2 at any time in the identified period.
1. Copyright © 2005. Rhoads GG et al. J Occup Environ Med. 2005;47(5):447–452. Reprinted with permission.
No hypoglycemia claima
Hypoglycemia Was Associated With
Decreased Health-Related Quality of Life1
RECAP-DM: observational, cross-sectional, multicenter study conducted in 7 European countries;
1,709 patients with T2DM who added a sulfonylurea or a TZD to ongoing metformin therapy
P<0.0001a
Without Symptoms
With Symptoms
P<0.0001b
With
Mild Symptoms
With
Moderate Symptoms
With
Severe Symptoms
EQ-5D=EuroQoL-5D, a standardized measure of health-related QoL; QoL=quality of life; RECAP-DM=Real-Life Effectiveness and Care Patterns of Diabetes Management ;T2DM=type 2
diabetes; TZD=thiazolidinedione; VAS=visual analog scale.
aBased on the t test of the null of no differences in the mean quality of life scores between patients with and without hypoglycemic symptoms. bBased on the F test of the joint hypothesis of no
differences in the mean quality of life scores across hypoglycemic symptom severity groups, including patients reporting no symptoms of hypoglycemia.
1. Álvarez Guisasola F et al. Health Qual Life Outcomes. 2010;8:86–93.
22
23
Hypoglycemia Was Associated With More
Short-Term Disability and Higher Health Care Costs1
Patients With
Hypoglycemiaa
n=442
Patients Without
Hypoglycemiaa
n=2222
P
≥1 episode of short-term
disability
47%
32%
P < 0.01
Days of short-term disability
per person-years
19.5
11.0
P < 0.01
$3169
$1812
P < 0.01
Annualized health care
expendituresb
 Incidence of disability increased from 0.8% to 4.7% the week after a hypoglycemic episode.
aIncludes
insulin-treated patients with type 1 and type 2 diabetes; US medical insurance claims.
short-term disability work loss.
Hypoglycemia occurrence=claims coded by (ICD-9-CM) 250.8, 251.1, or 251.2 at any time in the identified period.
1. Rhoads GG et al. J Occup Environ Med. 2005;47(5):447–452.
bAttributable to
24
Sweden: Health Care–Related Costs
and Hypoglycemia1
 Based on 300,000 patients with type 2 diabetes in Sweden, health care costs per year attributed
to hypoglycemic events in patients with type 2 diabetes are €4.25 million or €14.1/person using
cost-of-illness methodology.
Expected Yearly Cost of Hypoglycemic Events
Insulin Users
≤65 Years
Insulin Users
>65 Years
Oral
Treatment
Users
≤65 Years
Mild events, M€
0.35
0.26
0.09
0.03
0.73
Moderate events, M€
0.85
1.28
0.21
0.31
2.65
Severe events, M€
0.31
0.39
0.08
0.10
0.87
Total, M€
1.52
1.91
0.38
0.45
4.25
Per type 2 patient, €
45.7
33.7
8.0
5.6
14.1
Cost
Oral
Treatment
Users
>65 Years
All
Type 2
Diabetes
Patients
Mild, moderate, and severe episodes of hypoglycemia were considered in this analysis.
1. Reproduced with permission of John Wiley and Sons. Jonsson L et al. Value Health. 2006;9:193–198. Permission conveyed through Copyright Clearance Center, Inc.
Abdominal Obesity is Linked to a Higher
Risk for MI1
INTERHEART Study:
Case control study in 52 countries: 15152 cases vs 14820 controls
Abdominal obesitya leads to a significantly higher risk for MI:
OR (99%CI): 4.5 and 4.7 in W European and N American populations
MI=myocardial infarction; OR=odds ratio.
aWaist-to-hip ratio: upper tertile vs lowest tertile.
1. Yusuf S. et al. Lancet 2004; 364:937-52
25
A Brief History of Incretins
1932 – First
definition of
incretins3
1902 – First
observation of
intestinal effect on
pancreatic
secretion1,2
1966 – First
description of
DPP-46
1964 – Demonstration
of the incretin effect1,4,5
1986 – Incretin effect
shown to be reduced
in patients with type 2
diabetes7
1973 – GIP identified
as a human incretin1
1995 – DPP-4
identified as an
enzyme that
inactivates GIP and
GLP-19,10
1987 – GLP-1
identified as a
human incretin8
DPP-4=dipeptidyl peptidase-4; GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1.
1. Creutzfeldt W. Regul Pept. 2005;128:87–91. 2. Bayliss WM et al. J Physiol. 1902;28:325–353. 3. La Barre J. Bull Acad R Med Belg. 1932;120:620–634. 4. McIntyre N et al. Lancet.
1964;284:20-21..5. Elrick H et al. J Clin Endocr. 1964;24:1076–1082. 6. Hopsu-Havu VK et al. Histochemie. 1966;7(3):197–201. 7. Nauck M et al. Diabetologia. 1986;29:46–52. 8. Kreymann
B et al. Lancet. 1987;330:1300-1304..9. Kieffer TJ et al. Endocrinology. 1995;136;3585–3596. 10. Deacon CF et al. J Clin Endocrinol Metab. 1995;80:952–957.
Incretin Hormones Have Key Roles in
Glucose Homeostasis
GLP-1
GIP
 Is released from L cells in ileum and colon1,2
 Is released from K cells in duodenum1,2
 Stimulates insulin response from
beta cells in a glucose-dependent manner1
 Stimulates insulin response from
beta cells in a glucose-dependent manner1
 Inhibits glucagon secretion from
alpha cells in a glucose-dependent manner1
 Does not affect gastric emptying2
 Inhibits gastric emptyinga,1,2
 Has no significant effects on satiety or body
weight2
 Reduces food intake and
body weighta,2
GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1.
aEffects occur only with pharmacologic levels of GLP-1.
1. Drucker DJ. Diabetes Care. 2003;26:2929–2940. 2. Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.
28
DPP-4 Inhibitors: An Incretin-Based Glucose-Dependent
Mechanism for Improving Glycemic Control1–4
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; 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.
29
Sitagliptin Was Noninferior to Glipizide in
Reducing HbA1c at Week 52 (Primary End Point)1
Per-Protocol Population
LS mean change from baseline
at 52 weeks (for both groups): –0.7%
Change in HbA1c From Baseline (±SE), %
8.2
8.0
Sulfonylureaa + metformin (n=411 at 52 weeks)
7.8
Sitagliptinb + metformin (n=382 at 52 weeks)
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
Weeks
LS=least-squares; SE=standard error.
aSpecifically glipizide ≤20 mg/day; bSitagliptin 100 mg/day with metformin (≥1,500 mg/day).
Adapted from Nauck MA et al. Diabetes Obes Metab. 2007;9(2):194–205 with permission from Blackwell Publishing Ltd., Boston, MA.
46
52
30
HbA1c Reductions at Week 1041
2-Year Per-Protocol Population
(Patients Inadequately Controlled on Metformin)
Mean baseline HbA1c,%
7.30
7.31
LS Mean (95% CI) Change in HbA1c
From Baseline, %
0
–0.3
–0.5
Difference in LS Mean
HbA1c= –0.03
(95% CI: –0.13, 0.07)
Sitagliptin + metformin (n=248)
Glipizide + metformin (n=256)
–0.7
LS=least-squares; SD=standard deviation.
1. Seck T et al. Int J Clin Pract. 2010;64(5):562–576.
31
Sitagliptin vs Glipizide: Weight Change and
Incidence of Hypoglycemia1
Body weight at week 104
Hypoglycemia over 104 weeks
Between-groups difference = –2.3 kg
(95% CI: –3.0, –1.6)
Between-groups difference = –28.8%
(95% CI: –33.0, –24.5)
40
n=253
n=261
Patients With
at Least 1 Episode, %
LS Mean (±95% CI) Body Weight
Change From Baseline, kg
APaT Population
(Patients Inadequately Controlled on Metformin)
Sitagliptin + metformin
Glipizide + metformin
APaT=all-patients-as-treated; CI=confidence interval; LS=least-squares.
1. Seck T et al. Int J Clin Pract. 2010;64(5):562–576.
34,1
30
20
10
5,3
n=588
n=584
0
All Patients
Sitagliptin Was Assoicated With a Lower Risk of
Hypoglycemia Compared With Glipizide1
.005
Glipizide (age group <65)
Confirmed Hypoglycemiaa
n/Nb
316/461
Glipizide (age group ≥65 years)
Sitagliptin (age group <65 years)
132/123
27/468
.003
Sitagliptin (age group ≥65 years)
4/120
Risk
.004
.002
.001
0
6
aA hypoglycemic
7
8
Most recently measured HbA1c value (%)
event accompanied by a fingerstick blood glucose measurement of ≤70 mg/dL.
number of events/total number of patients in each subgroup.
1. Krobot K et al. Curr Med Res Opin. 2012;28:1–7.
bTotal
9
Rationale for Once-Daily Dosing of
Sitagliptin Based on DPP-4 Inhibition1
Single-dose study in healthy subjects (n=6)
DPP-4 Inhibition, %a
100
80
60
40
Sitagliptin 100 mg qd
20
0
0 1 2
4
6
DPP-4=dipeptidyl peptidase-4; qd=once daily.
aDPP-4 inhibition corrected for sample assay dilution.
1. Alba M et al. Curr Med Res Opin. 2009;25(10):2507–2514.
8
12
16
Hours Postdose
24
Select Pharmacodynamic Properties of DPP-4
Inhibitors
Sitagliptin
(Merck)1,2
Vildagliptin
(Novartis)3–5
Saxagliptin
(BMS/AZ)3,6
Alogliptin
(Takeda)7
Linagliptin
(BI)8,9
DPP-4 Peak
Inhibition
~97%
~95%
~80%
N/A
92%–94%
IC50 for DPP-4
18 nM
5.28 nM
3.37 nM
6.9 nM
~1 nM
IC50 for DPP-8
48,000 nM
1112 ± 50 nM
244 ± 8 nM
>100,000 nM
40,000 nM
(DPP-8/DPP-4)
(2600)
(210)
(72)
(>10,000)
(~40,000)
IC50 for DPP-9
>100,000 nM
66.2 ± 7.3 nM
104 ± 7 nM
>100,000 nM
>10,000 nM
(DPP-9/DPP-4)
(>5000)
(13)
(31)
(>10,000)
(>10,000)
IC50 for FAP
>100,000 nM7
89 nM
(>5000)
N/A
>100,000 nM
(FAP/DPP-4)
73,000 ± 8000 nM7
(>10,000)
(~89)
DPP-4=dipeptidyl peptidase-4.
1. Alba M et al. Curr Med Res Opin. 2009;25:2507–2514. 2. Kim D et al. J Med Chem. 2005;48:141–151. 3. Matsuyama-Yokono A et al. Biochem Pharmacol. 2008;76:98–
107. 4. European Public Assessment Report for Galvus. Available at: http://www.emea.europa.eu/humandocs/PDFs/EPAR/galvus/H-771-en6.pdf. Accessed May 4, 2011.
5. Ahrén B et al. J Clin Endocrinol Metab. 2004;89:2078–2084. 6. European Public Assessment Report for Onglyza. Available at:
http://www.emea.europa.eu/humandocs/PDFs/EPAR/onglyza/H-1039-en6.pdf. Accessed May 4, 2011. 7. Lee B et al. Eur J Pharmacol. 2008;589:306–314. 8. Heise T et al.
Diabetes Obes Metab. 2009;11:786–794. 9. Thomas L et al. J Pharmacol Exp Ther. 2008;325:175–182.
35
Sitagliptin Pooled Safety Analysis: Design1
19 double-blind, randomized, controlled clinical studies up to 2 years in durationa
 Sitagliptin as monotherapy
 Sitagliptin in initial combination with metformin (MET) or pioglitazone (PIO)
 Sitagliptin in combination with MET, PIO, sulfonylurea (SU) (±MET),
MET + rosiglitazone (ROSI), or insulin (±MET)
 Patients included in the non-exposed group received the following: placebo, MET,
PIO, SU (±MET), ROSI (±MET), or insulin (±MET)
Population (N=10,246)
 Sitagliptin 100 mg/day group (n=5429)
– 1805 patients were treated for at least 1 year
– 584 patients were treated for 2 years
– Mean duration of exposure was 282 days
 Non-exposed group (n=4817)
– 1320 patients were treated for at least 1 year
– 470 patients were treated for 2 years
– Mean duration of exposure was 259 days
aStudies
with results available as of July 2009.
1. Williams-Herman D et al. BMC Endocr Disord. 2010;10:7.
36
Sitagliptin Pooled Safety Analysis:
Summary of Adverse Experiences1
Incidence Rate per 100 Patient-Years
Sitagliptin
n=5429
Non-exposed
n=4817
Between-Groups
Difference (95% CI)a
1 or more AEs
153.5
162.6
–7.6 (–15.6, 0.3)
Drug-related AEsb
20.0
26.8
–6.4 (–8.7, –4.1)
Serious AEs
7.8
7.9
–0.1 (–1.3, 1.1)
Serious drug-related AEsb
0.4
0.3
0.1 (–0.1, 0.4)
Died
0.3
0.5
–0.2 (–0.5, 0.1)
Discontinued due to AEs
4.8
5.2
–0.5 (–1.5, 0.4)
Discontinued due to drug-related AEsb
1.7
2.3
–0.5 (–1.1, 0.1)
Discontinued due to serious AEs
1.7
1.7
–0.0 (–0.6, 0.5)
Discontinued due to serious drug-related AEsb
0.2
0.1
0.1 (–0.1, 0.3)
AE=adverse experience; CI=confidence interval.
aBetween-groups difference and 95% CI based on stratified analysis. Positive differences indicate that the incidence rate for the sitagliptin group was higher than the incidence rate for the nonexposed group. "0.0" and "–0.0" represent rounding for values that were slightly greater and slightly less than zero, respectively.
bConsidered by the investigator to be drug related.
1. Williams-Herman D et al. BMC Endocr Disord. 2010;10:7.
37
Sitagliptin and Metformin Target the Core
Metabolic Defects of Type 2 Diabetes
Sitagliptin improves
measures of (or
markers) beta-cell
function and
increases insulin
synthesis and
release.1
Beta-Cell
Dysfunction
Sitagliptin reduces HGO through
suppression of glucagon from alpha
cells.
1. Aschner P et al. Diabetes Care. 2006;29:2632–2637.
2. Abbasi F et al. Diabetes Care. 1998;21:1301–1305.
3. Kirpichnikov D et al. Ann Intern Med. 2002;137:25–33.
4. Zhou G et al. J Clin Invest. 2001;108:1167–1174.
5. Data on file, MSD
Insulin
Resistance
Metformin has insulinsensitizing properties.2–4
(Liver > Muscle, Fat)
Metformin decreases HGO by
targeting the liver to decrease
gluconeogenesis and
Hepatic Glucose
Overproduction (HGO) glycogenolysis.3
38
Initial Combination Therapy With Sitagliptin Plus
Metformin Provided Sustained HbA1c Reductions
Through 104 Weeks1
LS Mean HbA1c Change From Baseline, %
APT Population (Extension Study)
Sitagliptin 100 mg qd (n=50)
Sitagliptin 50 mg bid + metformin 500 mg bid (n=96)
Metformin 500 mg bid (n=64)
Metformin 1000 mg bid (n=87)
Sitagliptin 50 mg bid + metformin 1000 mg bid (n=105)
9.0
24-Week
Phase
8.5
Continuation
Phase
Extension
Study
Mean baseline HbA1c = 8.5%–8.7%
8.0
–1.1
7.5
–1.2
7.0
–1.3
–1.4
6.5
6.0
–1.7
0
6
12 18 24 30
38
46
54
Weeks
APT=all-patients-treated; bid=twice daily; LS=least-squares; qd=once daily.
1. Williams-Herman D et al. Diabetes Obes Metab. 2010;12(5):442–451.
62
70
78
91
104
39
Sitagliptin Is the Most Widely Prescribed DPP-4
Inhibitor With the Broadest Range of Indications
Sitagliptin: Powerful efficacy and proven experience as an adjunct to diet and exercise
in appropriate adult patients with type 2 diabetes
The clinical efficacy of Januvia has been demonstrated in the following uses:
Initial Monotherapy
 As initial therapy for appropriate patients
Initial Combination Therapy With 1 Agent
 As initial therapy in combination with metformin
 As initial therapy in combination with glitazone
Add-on Therapy to 1 Agent
 In combination with metformin
 In combination with sulfonylurea
 In combination with glitazone
 In combination with insulin
Add-on Therapy to 2 Agents
 In combination with sulfonylurea + metformin
 In combination with glitazone + metformin
 In combination with insulin + metformin
DPP-4=dipeptidyl peptidase-4.
40
Ongoing Cardiovascular Outcome Trials
With DPP-4 Inhibitors
TECOS1
Start: Dec 2008
Estimated Proj.
Completion: Dec 2014
N = 14,000
Trial Evaluating Cardiovascular Outcomes With Sitagliptin
Primary Outcome:
Time to first confirmed occurrence of CV event , a composite defined as CV-related death,
nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization
EXAMINE2,5
Start: Sept 2009
Estimated Proj.
Completion: Dec 2014
N = 5,400
Examination of Cardiovascular Outcomes: Alogliptin vs. Standard of Care in Patients With Type
2 Diabetes Mellitus and Acute Coronary Syndrome
Primary Outcome:
Time from randomization to the occurrence of the Primary Major Adverse Cardiac Events, a
composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke
SAVOR3,6
Start: May 2010
Estimated Proj.
Completion: April 2014
N = 16,500
Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial
Primary Outcome:
The primary efficacy outcome variable of the study is defined as the composite endpoint of
cardiovascular death, non-fatal myocardial infarction or non-fatal ischemic stroke
CAROLINA4
Start: Oct 2010
Estimated Proj.
Completion: Sept 2018
N = 6,000
Cardiovascular Outcome Study of Linagliptin vs. Glimepiride in Patients With Type 2 Diabetes
Primary Outcome:
Time to first occurrence of composite CV outcome, components of the primary composite
endpoint: CV death, non-fatal MI, non-fatal stroke and hospitalisation for unstable angina
pectoris
ClinicalTrials.gov NCT identifiers: 1. 00790205; 2. 00968708; 3. 01107886; 4. 01243424.
5. White W et al. Am Heart J. 2011;162:620-626; 6. Scirica B et al. Am Heart J. 2011;162:818-825.
Thank you!
Back up
Incretin Hormones Regulate
Insulin and Glucagon Levels
Hormonal signals
• GLP-1
• GIP
Glucagon
(GLP-1)
 cells
Neural signals
 cells
Gut
Pancreas
Insulin
(GLP-1,GIP)
Nutrient signals
●
Glucose
GLP-1 = glucagon-like peptide-1; GIP = glucose insulinotropic polypeptide
Adapted from Kieffer T. Endocrine Reviews. 1999;20:876–913. Drucker DJ. Diabetes Care. 2003;26:2929–2940. Nauck MA et al.
Diabetologia. 1993;36:741–744. Adapted with permission from Creutzfeldt W. Diabetologia. 1979;16:75–85. Copyright © 1979
Springer-Verlag.
13
Complementary Effects of Sitagliptin and Metformin on
Incretin Hormone Concentrations in Healthy Adult
Subjects1
Total GLP1
Active GLP-1
Active GIP
Sitagliptin
Metformin
Sitagliptin
+
Metformin
Observations in Healthy Subjects Compared
With Placeboa
 Increases active GLP-1 and GIP
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
In a study of drug-naïve patients with type 2 diabetes, active GLP-1 levels were increased more when
patients received both sitagliptin and metformin compared with either agent alone.2
GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1.
aData observations reported for post-prandial (4hr) weighted mean GLP-1 levels
1. Migoya EM. Clin Pharmacol Ther. 2010;88:801–808.
2. Data on file, MSD
44
Patients Were Worried About the Risk of
Hypoglycemia1
Respondents, %
Diabcare-Asia 2003 cross-sectional survey of
15,549 Asian patients with diabetes (96% type 2, 4% type 1);
answer to the question “I am worried about the risk of hypoglycemic events”
24% of patients in this study were on insulin therapy.
T2DM=type 2 diabetes.
1. Mohamed M. Curr Med Res Opin. 2008;24(2):507–514.
45
46
Patients With Type 2 Diabetes and Hypoglycemia Were
More Likely to Have Lower Health-Related Quality of Life1
Cross-sectional, internet-based surveya of 2,074 patients with type 2 diabetes
who were taking ≥1 oral antidiabetic agent (excluding insulin)
Adjusted effects of experiencing hypoglycemia symptoms on HRQL
P < 0.0001
P < 0.0001
P < 0.0001
P < 0.0001
P = 0.1627
EQ-5D Domains
CI=confidence interval; EQ-5D=EuroQoL-5D, a standardized measure of HRQL; HRQL=health-related quality of life; OR=odds ratio.
aSurvey used a 30-item Diabetes Symptom Measure (DSM) to assess the frequency of cognitive and physiological symptoms in the 2 weeks prior to the survey.
Data were not verified against clinician diagnoses or chart reviews, nor were reports of low blood sugar confirmed by blood glucose monitoring.
1. Williams SA et al. Diab Res Clin Pract. 2011;91:363–370.
47
In a Longitudinal Study, a History of Severe Hypoglycemia
Was Associated With a Greater Risk of Dementia1
Attributable risk of dementia with any hypoglycemia: 2.39% (1.72–3.01)a
4.34
4.28
n=258
n=205
1.64
n=1,002
The clinical significance of minor glycemic episodes with dementia risk is unknown.
aAttributable risk
calculated as difference between rate in group and rate in reference group (0 hypoglycemic events).
1. Whitmer RA et al. JAMA. 2009;301:1565–1572.
Earlier and Appropriate Intervention May
Improve Patients’ Chances of Reaching Goal1
Published Conceptual Approach
Diet and
OAD
exercise monotherapy
OAD
OAD
up-titration combination
OAD +
basal insulin
OAD +
multiple daily
insulin
injections
10
A1C,%
9
Mean A1C
of patients
8
A1C goal of 7%
7
6
Duration of Diabetes
Conventional stepwise
treatment approach
Earlier and proactive
intervention approach
OAD=oral antidiabetic agent.
1. Adapted from Del Prato S et al. Int J Clin Pract. 2005;59(11):1345–1355. Copyright © 2005. Adapted with permission of Blackwell Publishing Ltd.
Severe Hypoglycemia May Cause a Prolongation
of QT Interval in Patients With Type 2 Diabetes1
49
All patients participated in one hypoglycemic clamp while on treatment with insulin
only, and another during combined glibenclamide and insulin therapy.
P<0.0001
460
450
P=0.0003
End of clamp (t=150 min)
Mean QT interval, ms
440
430
420
Baseline (t=0)
P=NS
410
400
390
380
370
 Significant prolongation
of QT interval after
hypoglycemic clamps
– Increased risk of
arrhythmias
360
0
Euglycemic clamp Hypoglycemic clamp
Hypoglycemic clamp
(n=8)
2 weeks after
6–8 months after
glibenclamide withdrawal resuming glibenclamide
(n=13)
(n=13)
NS=not significant.
Thirteen patients with type 2 diabetes taking combined insulin and glibenclamide treatment were studied during hypoglycemia; 8 participated in the euglycemic experiment clamped between 5.0
and 6.0 mmol/L. The aim was to achieve stable hypoglycemia between 2.5 and 3.0 mmol/L (45 and 54 mg/dL) during the last 60 minutes of the experiment.
1. Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307.
Severe Hypoglycemia May Cause a Prolongation
of QT Interval in Patients With Type 2 Diabetes1
50
All patients participated in one hypoglycemic clamp while on treatment with insulin
only, and another during combined glibenclamide and insulin therapy.
P<0.0001
460
450
P=0.0003
End of clamp (t=150 min)
Mean QT interval, ms
440
430
420
Baseline (t=0)
P=NS
410
400
390
380
370
 Significant prolongation
of QT interval after
hypoglycemic clamps
– Increased risk of
arrhythmias
360
0
Euglycemic clamp Hypoglycemic clamp
Hypoglycemic clamp
(n=8)
2 weeks after
6–8 months after
glibenclamide withdrawal resuming glibenclamide
(n=13)
(n=13)
NS=not significant.
Thirteen patients with type 2 diabetes taking combined insulin and glibenclamide treatment were studied during hypoglycemia; 8 participated in the euglycemic experiment clamped between 5.0
and 6.0 mmol/L. The aim was to achieve stable hypoglycemia between 2.5 and 3.0 mmol/L (45 and 54 mg/dL) during the last 60 minutes of the experiment.
1. Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307.
Antecedent Hypoglycemia Impaired Markers
of Autonomic Function1
Measures of autonomic function in 20 young healthy subjects after antecedent
euglycemic ( ■) or hypoglycemic ( o ) clamp studies.
Baroreflex sensitivity
Sympathetic response to
hypotensive stress
Sympathetic Burst Frequency,
bursts/minute
P < 0.04
Cardiac Vagal Baroreflex
Sensitivity, ms/mmHg
20.0
17.5
15.0
12.5
0.0
5.0
2.8
Antecedent Clamp
Glucose (mmol/L)
CVD=cardiovascular disease.
1. Adler GK et al. Diabetes. 2009;58:360–366.
70
60
50
P < 0.01
40
30
20
0
Baseline
PostNitroprusside
51
52
pmol/L
pmol/L
20
15
10
5
0
–30 0
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
40
30
20
* 10
0
20
15
10
5
*
Infusion
60
120
Minutes
180
240
Placebo
GLP-1
*P<0.05
Patients with
type 2 diabetes (N=10)
When glucose levels
approach normal values,
insulin levels decrease.
pmol/L
Glucagon
250
200
150
100
50
0
*
250
200
150
* 100
50
0
mU/L
Insulin
15.0
12.5
10.0
7.5
5.0
2.5
0
mg/dL
Glucose
mmol/L
Glucose-Dependent Effects of GLP-1 Infusion on Insulin
and Glucagon Levels in Patients With Type 2 Diabetes1
When glucose levels
approach normal values,
glucagon levels rebound.
0
1. Adapted with permission of Springer Verlag. Adapted from Nauck MA et al. Diabetologia. 1993;36(8):741–744. Copyright © 1993 Springer Verlag.
Permission conveyed through Copyright Clearance Center, Inc.
56
Sitagliptin as Add-on Therapy to Insulin vs Insulin Doseincrease Therapy in Uncontrolled Korean T2DM: Study Design1
24-Week Insulin ± Sitagliptin Dose Period
• Patients with type 2 diabetes
• Age 30–70
• Receiving insulin (including
glargine, glargine + rapid-acting
insulin, and combination of NPH
insulin and regular insulin) for
≥ 3 months at a dose of 10 U/day,
and for at least 4 weeks prior to
enrollment
• FPG < 15 mmol/L (270 mg/dL)
Sitagliptin Adding Regimen 100 mg qd (n=70)
R
Insulin Increasinga Regimen (n=70)
• BMI 18–35 kg/m2
• HbA1c ≥7.5% and ≤11%
Screening visit
Week –4
Randomization
aSubjects
Week 12
Week 24
were guided to increase their daily insulin dose by 10% at random and then by a further 10% at 12 weeks if their HbA1c ≥7%. In addition to this 20% increase, subjects were allowed
to adjust their insulin dose by 2 U every week, based on the self-monitoring of their blood glucose.
BMI=body-mass index; FPG=fasting plasma glucose; T2DM=type 2 diabetes mellitus; qd=once daily.
1. Hong ES et al. Diabetes Obes Metab. Accepted Article doi: 10.1111/j.1463-1326.2012.01600.x.
Add-on Sitagliptin vs Insulin Increasing:
Study Endpoints1
 The primary endpoint of the study was to compare changes in HbA1c
levels after 24-weeks of add-on sitagliptin or insulin increasing
treatment
 Secondary efficacy endpoints included:
– The proportion of participants who had an HbA1c ≤ 7% without hypoglycemia
– The change in body weight
– The change in insulin dose
 Safety endpoints were:
–
–
–
–
Adverse events
Serious adverse events
Hypoglycemia
Severe hypoglycemic events
1. Hong ES et al. Diabetes Obes Metab. Accepted Article doi: 10.1111/j.1463-1326.2012.01600.x.
57
58
Addition of Sitagliptin Significantly Decreased HbA1c
Compared to Patients With Insulin Increasing at Week 241
HbA1c, %
10
Sitagliptin Add-on
Insulin Increasing
-0.22%a
(95% CI, -0.55, 0.31)
9
-0.42%b
(95% CI, -0.91, 0.11)
-0.63%a
(95% CI, -0.93, -0.38)
8
0
12
Time (weeks)
CI=confidence interval
aP < 0.05 vs. baseline; bP < 0.05 between arms.
1. Hong ES et al. Diabetes Obes Metab. Accepted Article doi: 10.1111/j.1463-1326.2012.01600.x.
24
59
Significantly More Subjects Adding
Sitagliptin Achieved HbA1c ≤ 7%1
Proportion of Subjects
Achieving HbA1c ≤ 7%, %
P=0.021
All Subjects
1. Hong ES et al. Diabetes Obes Metab. Accepted Article doi: 10.1111/j.1463-1326.2012.01600.x.
Addition of Sitagliptin Was Associated With a Lower
Incidence of Hypoglycemia and Reduced Body Weight vs
the Insulin Increasing Regimen1
Body Weight Change at Week 24
Hypoglycemia Over 24 Weeks
20
17.5
18
16
Sitagliptin Add-on
Insulin Increasing
14
12
10
8
8.2
P <0.05
6
4.8
4
1.6
2
0
Hypoglycemia
Change in Body Weight From Baseline, kg
Patients With ≥1 Hypoglycemic Episode, %
P <0.05
Severe Hypoglycemia
1. Hong ES et al. Diabetes Obes Metab. Accepted Article doi: 10.1111/j.1463-1326.2012.01600.x.
 = –1.8 kg
(P <0.05)
Sitagliptin Add-on
Insulin Increasing
60
61
Mean Daily Insulin Use Increased Significantly
in the Insulin Increasing Patients1
-2.5 (95% CI, -4.5, -1.3)
10.1 (95% CI, 4.5, 14.9)
Mean Insulin Use (U/day)
25% increase
from baseline
Week 0
aP<0.05 for
Week 24
the between-treatment difference.
1. Hong ES et al. Diabetes Obes Metab. Accepted Article doi: 10.1111/j.1463-1326.2012.01600.x.
Week 0
Week 24
62
Sitagliptin Adding vs Insulin Increasing in
T2DM: Adverse Event Summary1
Sitagliptin Add-on
Insulin Increasing
N
%
N
%
One or more AEs
21
34.4
23
36.5
Drug-related AEs
9
14.8
8
12.7
Serious AEs
3
4.9
4
6.3
Drug-related serious AEs
1
1.6
4
6.3
Discontinued due to AEs
6
9.8
6
9.5
Discontinued due to
drug-related AEs
2
3.3
4
6.3
AE=adverse event; T2DM=type 2 diabetes mellitus.
1. Hong ES et al. Diabetes Obes Metab. Accepted Article doi: 10.1111/j.1463-1326.2012.01600.x.
63
Conclusions1
 In this 24-week study, the addition of sitagliptin in patients with uncontrolled
T2DM on insulin therapy led to:
– Significantly decreased HbA1c levels compared with patients with
increasing doses of insulin
– Significantly more subjects able to achieve HbA1c ≤ 7%
– A lower incidence of hypoglycemia vs. increasing doses of insulin
– Reduced body weight compared with subjects in the insulin increasing
group
– A modest decrease in the insulin dose compared with a significant
increase of 25% in the insulin dose of the insulin increasing arm
– A similar AE frequency
AE=adverse event; T2DM=type 2 diabetes mellitus.
1. Hong ES et al. Diabetes Obes Metab. Accepted Article doi: 10.1111/j.1463-1326.2012.01600.x.
Sitagliptin Pooled Analysis: No Difference in
Incidence of Pancreatitis Between Sitagliptin and
Non-exposed Groups1
Incidence Rate per 100 Patient-Years
Sitagliptin
n=5,429
Non-exposed
n=4,817
Between-Groups
Difference, (95% CI)a
Pancreatitis
0.08
0.10
–0.02 (–0.20, 0.14)
Chronic pancreatitis
0.04
0.03
0.02 (–0.11, 0.13)
Adverse Experience
 Preclinical and clinical trial dataa with sitagliptin to date do not indicate
an increased risk of pancreatitis in patients with type 2 diabetes
treated with sitagliptin.
CI=confidence interval.
aData available through July 2009.
1. Engel SS et al. Int J Clin Pract. 2010;6497):984–990.
64
66
Sitagliptin Pooled Safety Analysis: No Difference in
MACEa Between Sitagliptin and Non-exposed Groups1
Incidence Rate per 100 Patient-Years
Adverse Experience
MACE
Sitagliptin
n=5429
Non-exposed
n=4817
Between-Groups
Difference
(95% CI)b
0.6
0.9
–0.3 (–0.7, 0.1)
Relative Risk Ratio
(95% CI)
0.68 (0.41, 1.12)
 Custom MACE analysis with terms similar to those requested by the US Food and
Drug Administration for recent MACE analyses with other antihyperglycemic agents
 Total of 64 patients with at least 1 MACE-related event
CI=confidence interval; MACE=major adverse cardiovascular events.
aThere was no adjudication of any cardiac event.
bBetween-groups difference and 95% CI based on stratified analysis. Positive differences indicate that the incidence rate for the sitagliptin group
was higher than the incidence rate for the non-exposed group.
1. Williams-Herman D et al. BMC Endocr Disord. 2010;10:7.
DPP-4 Inhibitors Differ in Molecular
Structures and Pharmacologic Properties
Chemical
Class
β-Phenethylamines1
Generic
Name
Sitagliptin2,3
Molecular
Structure
F
F
Cyanopyrrolidines
Vildagliptin2,4,5
Saxagliptin2,6,7
H
FNH2O
N
N
N N
CF3
N
NC
O
N
H
HO
H NH2
N
NC
O
Aminopiperidine8
Xanthine
Alogliptin9,10
Linagliptin11,12
O
O
CN
H3C N N
O
N
N
N
N
N
O
N
NH2
HO
NH2
DPP-4
Inhibitory
Activity
(IC50)
Half-life
N
N
9.96 ± 1.03 nM
5.28 ± 1.04 nM
3.37 ± 0.90 nM
6.9 ± 1.5 nM
~1 nM
12.4 h
~2–3 h
2.5 h (parent)
3.1 h (metabolite)
12.4–21.4 h
113–131 h
DPP-4=dipeptidyl peptidase-4. IC50 =half maximal inhibitory concentration
1. Kim D et al. J Med Chem. 2005;48:141–151. 2. Matsuyama-Yokono A et al. Biochem Pharmacol. 2008;76:98–107. 3. JANUVIA EU-SPC 2010.
4. Villhauer EB et al. J Med Chem. 2003;46:2774–2789. 5. Galvus EU-SPC 2010. 6. Augeri DJ et al. J Med Chem. 2005;48:5025–5037. 7. Onglyza
EU-SPC 2010. 8. Feng J et al. J Med Chem. 2007;50:2297–2300. 9. Lee B et al. Eur J Pharmacol. 2008;589:306–14. 10. Christopher R et al. Clin
Ther. 2008;30:513–527. 11. Thomas L et al. J Pharmacol Exp Ther. 2008;325:175–182. 12. Heise T et al. Diabetes Obes Metab. 2009;11:786–794.
Pharmacokinetic Properties of DPP-4
Inhibitors
Sitagliptin
(Merck)1
Vildagliptin
(Novartis)2
Saxagliptin
(BMS/AZ)3
Alogliptin
(Takeda)5
Linagliptin
(BI)6–8
Absorption tmax
(median)
1–4 h
1.7 h
2 h (4 h for active
metabolite)
1–2 h
1.34–1.53 h
Bioavailability
~87%
85%
>75 %4
N/A
29.5%
Half-life (t1/2) at
clinically relevant
dose
12.4 h
~2–3 h
2.5 h (parent)
3.1 h (metabolite)
12.4–21.4 h
(25–800 mg)
113–131 h
(1–10 mg)
Distribution
Metabolism
Elimination
38% protein bound
9.3% protein bound
Low protein binding
N/A
Prominent
concentrationdependent protein
binding:
<1 nM: ~99%
>100 nM: 70%–80%
~16% metabolized
69% metabolized
mainly renal
(inactive metabolite)
Hepatic
(active metabolite)
CYP3A4/5
<8% metabolized
~26% metabolized
Renal 85%
(23% unchanged)
Renal 75%
(24% as parent; 36% as
active metabolite)
Renal
(60%–71%
unchanged)
Feces 81.5%
(74.1% unchanged);
Renal 5.4%
(3.9% unchanged)
Renal 87%
(79% unchanged)
DPP-4=dipeptidyl peptidase-4.
1. JANUVIA EU-SPC 2010. 2. Galvus EU-SPC 2010. 3. Onglyza EU-SPC 2010. 4. EPAR for Onglyza. Available at: http://www.ema.europa.eu/.
Accessed September 17, 2010. 5. Christopher R et al. Clin Ther. 2008;30:513–527. 6. Heise T et al. Diabetes Obes Metab. 2009;11:786–794.
7. Reitlich S et al. Clin Pharmacokinet. 2010;49:829–840. 8. Fuchs H et al. J Pharm Pharmacol. 2009;61:55–62.
69
Selectivity:
Comparative Toxicity Studies1
2-Week Rat Study at 10, 30 100 mg/kg/day; Acute dog toxicity at 10 mg/kg
2-Week Rat
Toxicity
QPP
Selective
DPP-8/9
Selective
Nonselective
Alopecia


Thrombocytopenia


Anemia


Enlarged spleen


Mortality




DPP-4
Selective
Acute Dog Toxicity
Bloody diarrhea
Conclusion: Inhibition of DPP-8 and/or DPP-9 resulted in multiorgan
toxicities in rats and dogs.
DPP=dipeptidyl peptidase; QPP=quiescent cell proline dipeptidase.
1. Lankas GK et al. Diabetes. 2005;54:2988–2994.
71
Saxagliptin Was Noninferior to Sitagliptin in
Reducing HbA1c at 18 Weeks1
Primary End Point (Per-Protocol Population; on background of metformin therapy)
Change From Baseline in
Adjusted Mean HbA1c (SE), %
Mean baseline HbA1c, %
0.00
7.69
7.68
Sitagliptin 100 mg + metformin
n=343
n=334
Saxagliptin 5 mg + metformin
–0.15
–0.30
–0.45
–0.60
–0.75
–0.52
(95% CI: –0.60, –0.45)
–0.62
(95% CI: –0.69, –0.54)
0.09 (95% CI: –0.01, 0.20)a
(Prespecified noninferiority
margin=0.30%)
CI=confidence interval; FAS=full-analysis-set; SE=standard error.
aDifference in adjusted change from baseline vs sitagliptin + metformin.
1. Scheen AJ et al. Diabetes Metab Res Rev. 2010;26(7):540–549.
In the FAS population,
the adjusted mean HbA1c
reductions from baseline to
week 18 were observed for
sitagliptin 100 mg
(-0.59%) and saxagliptin 5 mg
(-0.42%). Difference between
groups: 0.17% (95% CI: 0.06,
0.28)
72
FPG Reductions With Sitagliptin vs. Saxagliptin
at 18 Weeks1
Secondary End Point (FAS Population; on background of metformin therapy)
FPG LS Mean (±SE) Change
From Baseline, mmol/L
Mean baseline FPG, mmol/L
0
8.89
8.86
n=392
n=397
–0.3
–0.6
–0.60
–0.9
–0.90
–1.2
0.30 (95% CI: 0.08, 0.53)a
CI=confidence interval; FAS=full-analysis-set; FPG=fasting plasma glucose; LS=least squares; SE=standard error.
aBetween-groups difference vs sitagliptin + metformin.
1. Scheen AJ et al. Diabetes Metab Res Rev. 2010;26(7):540–549.
Sitagliptin 100 mg
+ metformin
Saxagliptin 5 mg
+ metformin
OPTIMA : Optimized Glycemic Control With
Vildagliptin vs. Sitagliptin - Study Design1
CGM for
3 days
Inclusion Criteria:
• Age > 18 yrs
• HbA1c between 6.5
and 8.0%
• BMI between 22
and 45 kg/m2
• Currently on stable,
maximum tolerated
metformin dose
CGM for
3 days
Vildagliptin + Metformin (N=19)
CGM for
3 days
R
2-4 Weeks
Sitagliptin + Metformin (N=19)
8 Weeks
CGM=continuous glucose monitoring.
1. Guerci B et al. French Diabetes Society (SFD) Congress. Nice, France. 2012. Poster 299.
74
OPTIMA : Optimized Glycemic Control With
Vildagliptin vs. Sitagliptin - Study Objectives1
 Primary Objective:
– Change in mean amplitude of glycemic excursions (MAGE) after 8
weeks of treatment
 Secondary Objectives:
– Time spent in the optimal glycemic range, ≥ 70 and ≤ 140 mg/dL
– Time spent in hyperglycemic range, ≥140 and ≥180 mg/dL
– Time spent in hypoglycemic range, < 70 mg/dL
1. Guerci B et al. French Diabetes Society (SFD) Congress. Nice, France. 2012. Poster 299.
75
OPTIMA : Glycemic Variability Results Were Similar
Between Sitagliptin and Vildagliptin Treated Groups1
P=0.83
Variable, mg/dL
At baseline
At 8 weeks
P=0.61
MAGE
SD of 24-h
Mean Glycemia
BID=twice daily; MAGE=mean amplitude of glycemic excursions; MODD=mean of daily differences; QD=once daily; SD=standard deviation.
1. Guerci B et al. French Diabetes Society (SFD) Congress. Nice, France. 2012. Poster 299.
P=0.89
MODD