Ueda2015 diabetes control dr.lobna el-toony

Prof. Lobna El Toony
Professor of Endocrinology
Head of Internal Medicine Department
Assiut University
Diabetes Control:
Efficacy & safety come together

Topics For Discussion:
 Diabetes Burden & Clinical benefit of Diabetes Control
 Challenges with traditional oral AHA
 How can we solve challenges……achieve the balance
 Cardiovascular safety of AHA
 Clinical evidence of sitagliptin : Efficacy & safety
 Evolution of Guidelines & Treatment Algorithm for
management of T2DM

2014
Diabetes is a huge and growing problem…
2035

IDF. Diabetes Atlas 5th Ed. 2011
The Diabetes Epidemic: Global Projections, 2010–2030

NHANES and EURIKA: HbA1c Attainment
52.2
39.7
48.4
41.5 40.6
43.8 41.9
26.2
33.7
23.4
41.8
26 27.7
0
10
20
30
40
50
60
70
80
90
100
Country
HbA1cAttainment,%
US (n=1,444)
AUS (n=146)
BEL (n=173)
FRA (n=144)
GER (n=256)
GRE (n=176)
NOR (n=142)
RUS (n=95)
SPA (n=182)
SWE (n=164)
SWI=205)
TUR (n=210)
UK (n=153)
6
EURIKA (Europe)2: May 2009–January 2010
HbA1c <6.5%
EURIKA=European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice; NHANES=National Health and Nutrition Examination Survey.
1. Ali MK et al. N Engl J Med. 2013;368:1613–1624.
2. Banegas JR et al. Eur Heart J. 2011;32:2143–2152.
NHANES (US)1: 2007–2010
HbA1c <7.0%

UKPDS: Worse HbA1c Control and
Increased Diabetes-Related Complications
UKPDS=United Kingdom Prospective Diabetes Study.
Data adjusted for age, sex, and ethnic group, expressed for white men aged 50–54 years
at diagnosis and with mean duration of diabetes of 10 years.
Stratton IM et al. UKPDS 35. BMJ 2000;321:405–412.
EVERY 1%
increase in HbA1c
INCREASED RISK
(P<.0001)
1%
Diabetes-
related
deaths
Myocardial
infarctions
Microvascular
complications
Amputations or deaths
from peripheral
vascular disorders
Relative Risk
N=3642

Challenges with Traditional oral AHA
• Hypoglycemia
• Weight Gain
• B-Cell exhaustion
• Cardio-vascular safety

HbA1c=haemoglobin A1c; OAD, oral antidiabetic drugs.
Jacob AN, et al. Diabetes Obes Metab. 2007; 9:386–393;
Kahn SE, et al. N Engl J Med. 2006; 355: 2427–2443;
Wright AD, et al. J Diabetes Complications. 2006; 20: 395–401.
Decreasing HbA1c is associated with
increased risks of hypoglycaemia and
weight gain
Weight gain
and
hypoglycaemia
Bodyweight
HbA1c
Plasmaglucose

Potential Complications and Effects of
Severe Hypoglycemia
11
Plasma glucose level
10
20
30
40
50
60
70
80
90
100
110
1
2
3
4
5
6
mg/dL
mmol/L
1. Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307.
2. Cryer PE. J Clin Invest. 2007;117:868–870.
Arrythmia1 Neuroglycopenia2
 Abnormal prolonged
cardiac repolarization —
↑ QTc and QT dispersion
 Sudden death
 Cognitive impairment
 Unusual behavior
 Seizure
 Coma
 Brain death
Underlying endothelial
dysfunction leading to
decreased
vasodilatation may
also contribute to
cardiovascular risk.

Hypoglycemia Is Associated With
Increased Health Care Costs1
Hospital Outcomes,
mean
Patients With
Hypoglycemia
Patients Without
Hypoglycemia
Between-Group
Difference or Odds
Ratio (unadjusted)a Pn
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
 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
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.
Base-case analysis (blood glucose <70 mg/dL)

Hypoglycaemia
1Briscoe VJ, et al. Clin Diabetes 2006;24:115–21;
2Cryer PE. Diabetologia 2002;45:937–48
A major limiting factor to achieve intensive
glycaemic control in people with T2DM1
Hypoglycaemia makes clinicians less likely
to implement glycaemic targets2

Challenges with Traditional oral AHA
 Hypoglycemia
 Weight Gain
 B-Cell exhaustion
 Cardio-vascular safety

10 µm
~ 10,000
granules
Micrograph: Lelio Orci, Geneva
The normal beta-cell
Presented by Pr Philippe Halban
at the 1st Amsterdam Diabetes Meeting, March 30-April 1, 2006
Pancreas consists of
1 million islets of
Langerhans
Start to develop from
week 9-11 gestation

 Half-life of ~30 days
 Apoptosis is the major mechanism of death
normal apoptotic
New beta-cells by:
*Replication
*Neogenesis

Factors for progressive loss of B-
cell function & mass
Glucotoxicity Lipotoxicity
l
ApoptosisInsulin
Secretion
Prentki M et al. Diabetes. 2002;51(suppl 3):s405-s413.
Amyloid depositionInflamatory
Cytokines& ROS

Global cardiometabolic risk*
Gelfand EV et al, 2006; Vasudevan AR et al, 2005
* working definition

Therapy:
What More Could We
Possibly Want?
Animal Insulin
1922 1950’s 1982-85 1995 1996 2001 2003 2005 2007 2009
Sulfonylurea
Human Insulin
Metformin
Lispro
Glitazones
Glinides
Aspart
Exenatide
Pramlintide
Detemir
Sitagliptin
Bromocriptine
Saxagliptin
2013
Liraglutide
SGLT-2 inhib
11-β-HSD1 inhib
The End of Protocol
Driven Therapy
Weekly Exenatide
Degludec
Glucagon R antangonists

Clinical trials to prevent cardiovascular
disease in patients with T2D
1998 2008 2013
UKPDS
ACCORD
VADT
ADVANCE
SAVOR
EXAMINE

Lessons learned from UKPDS
•Lowering HbA1c at 7.4% is beneficial to
prevent diabetes complications.
•Benefits can be sustained together with a
continuous effort in lowering HbA1c.
•Metformin is an effective drug within this
strategy (=> Guidelines and WHO list).

• 10,251 type 2 diabetics.
• Average age is 62 years.
• 10 years of Diabetes.
• Median HbA1c level 8.1%
• 35% already had
diagnosed CVD.
• Or two CVD risk factors
[Lipids, BP, smoking, or
obesity].
New England Journal of Medicine. N Engl J Med. 2008;358:2545-
ACCORD trial

Results: Cardiovascular
mortality
New England Journal of Medicine. N Engl J Med. 2008;358:2545-New England Journal of Medicine. N Engl J Med. 2008;358:2545-
P=0.02
+35%

•Veterans with type 2
diabetes (N = 1,791)
•Duration is 10 years.
•HbA1c > 8.3%.
•40% has already CV
events.
•Other Risk Factors
[HTN, Lipids obesity].
Duckworth et al, New eng J Med 2008; ahead of print
VADT trial

Results: Cardiovascular
mortality
Duckworth et al, New eng J Med 2008; ahead of print
+32%P=NS

Position statement
A position statement of ADA, ACC and AHA. Diabetes Care, volume 32; 1, January 2009.

30
Impact of Intensive vs Conventional Glycemic-Lowering
Strategies on Risk of CV Outcomes Is Unclear
Study
Diabetes
Duration
(mean)
Antihyperglycemic
Medicationa
Follow-up
(median)
HbA1c: Baseline,
Between-arm
Difference
Microvascular CVD Mortality
UKPDS1
Newly
diagnosed
SU/insulin or metformina vs
dietary restriction
10 years
7.1% (all patients)b,
–0.9%c ↓ ↔ ↔
UKPDS
Long-term
follow-up2
10 years post
intervention
No difference in
HbA1c between
treatment armsd
↓ ↓ ↓
ADVANCE3 8 years
Intensive glucose control
including gliclazide vs
standard treatment
5 years
7.5% (both arms)b,
–0.8%d ↓ ↔ ↔
ACCORD4,5 10 years Multiple drugs in both arms 3.4 years
8.1% (both arms)e,
–1.1%c ↓ ↔ ↑
VADT6 11.5 years Multiple drugs in both arms 5.6 years
9.4% (both arms)b,
–1.5%d ↔ ↔ ↔
aObese patients; bMean baseline HbA1c; cMedian between-arm difference; dMean between-arm difference; eMedian baseline HbA1c.
CV = cardiovascular; UKPDS = United Kingdom Prospective Diabetes Study (UKPDS); ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron
Modified Release Controlled Evaluation; ACCORD = Action to Control Cardiovascular Risk in Diabetes; VADT = Veterans Affairs Diabetes Trial.
1. UKPDS Group. Lancet. 1998;352:837–853. 2. Holman RR et al. N Engl J Med. 2008;359:1577–1589. 3. ADVANCE Collaborative Group et al. N Engl J Med. 2008;358:2560–2572. 4. Gerstein
HC et al. N Engl J Med. 2008;358:2545–2559. 5. Ismail-Beigi F et al. Lancet. 2010;376:419–430. 6. Duckworth W et al. N Engl J Med. 2009;360:129–139.
Lowering HbA1c may prevent macrovascular disease if started early,
but the effects may not be apparent for a very long time

31
Impact of Antihyperglycemic Medications’ Mechanisms of
Action on Risk of CV Outcomes Is Unclear
Study
Intervention
(vs active/PBO)
Population
HbA1c:
Baseline,
between-arm
difference
Primary end point
Primary end
point
HR (95% CI)
P value
Heart failure
end point
HR (95% CI)
P value
RECORD1
Rosiglitazone +
SU/Metformin vs
SU/Metformin
No requirement
for CV disease
or risk factorsa
7.9%,
–0.3%b,c CV hospitalization, CV death
0.99
(0.85–1.16)
P=0.93
2.10
(1.35–3.27)e
P=0.001
ProACTIVE2,3 Pioglitazone vs
Placebo
Extensive
evidence or
history of
macrovascular
disease
7.8%–7.9%,
–0.5%b,d
Death from any cause, nonfatal MI
(including silent MI), stroke, ACS,
leg amputation, revascularization of
coronary or leg arteries
0.90
(0.80–1.02)
P=0.095
1.41
(1.10–1.80)g
P=0.007
SPREAD-
DIMCAD4
Metformin
vs Glipizide
History of CAD
7.6%.
–0.1%c
Death from any cause, CV death,
nonfatal MI/stroke, PTCA, CABG
0.54
(0.30–0.90)
P=0.026
0.82
(0.31–2.13)g
P=0.677
aExclusions were hospitalization for a major CV event 3 months before the trial, planned CV intervention, and presence, history, or treatment for heart
failure; bP<0.0001; cMean between-arm difference; dMedian between-arm difference; eFatal and nonfatal HF; fSerious HF; gNew or worsening HF.
CV = cardiovascular; PBO = placebo; HR = hazard ratio; CI = confidence interval; SU = sulfonylurea; ACS = acute coronary syndrome; CAD = coronary
artery disease; PTCA = percutaneous transluminal coronary angioplasty; CABG = coronary artery bypass grafting; HF = heart failure.
1. Home PD et al. Lancet. 2009;373:2125–2135. 2. Dormandy JA et al. Lancet. 2005;366:1279–1289. 3. Erdmann E et al. Diabetes Care. 2007;30:2773–2278. 4. Hong J et al. Diabetes
Care. 2013;36:1304–1311.

32
Reasons?
Drugs used?
Increase in hypoglycaemia?
Increase in weight?
Too rapid reduction in HbA1c?
Time of treating Hyperglycemia ?

EASD Barcelona 2013 Abstract 201
"I am bewildered it's still being used," Dr. Currie told Medscape Medical News.
"People should avoid using a drug where the balance of evidence, at the
moment, demonstrates that it kills people."
Does SU use increase mortality….?

39
DPP-4 Inhibitor CV Outcome Trials
EXAMINE and SAVOR-TIMI:
Hospitalization for Heart Failure
SAVOR-TIMI3
Saxagliptin
n=8,280
Placebo
n=8,212
HR (95% CI)
HHF 3.5% 2.8% 1.27 (1.07–1.51)
EXAMINE1,2
Alogliptin
n=2,701
Placebo
n=2,679
HR (95% CI)
HHFa 3.9% 3.3% 1.19 (0.89–1.58)
SAVOR-TIMI: Hospitalization for HF was
significantly increased with saxagliptin
compared with placebo3
– Mortality due to HF was not significantly
different between saxagliptin and placebo
(0.5% for both)3
aPost-hoc analysis.
EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary
Syndrome; SAVOR-TIMI = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial-Thrombolysis in Myocardial
Infarction; HHF = hospitalization for heart failure; HR = hazard ratio; CI = confidence interval; HF = heart failure.
1. White WB et al. N Engl J Med 2013;369:1327–1335. 2. Sanon VP et al. Clin Diabetes. 2014;32:121–126. 3. Scirica BM et al. N Engl J Med 2013;369:1317–1326.
EXAMINE: In a post-hoc analysis, there
was a trend (P=NS) for increased
hospitalization for HF with alogliptin
compared with placebo2

40
FDA Advisory Committee reviews SAVOR outcomes
study results for Saxagliptin and (saxagliptin /
metformin XR) 14th of April 2015
• A New report from FDA suggests that use of the diabetes drug saxagliptin
was associated with "significant" increases in all-cause death, not just
heart problems, in a clinical trial.
• The report was released ahead of an April 14 meeting of outside advisers
who will discuss the heart effects of the two drugs are DPP-4 inhibitors,
(saxagliptin and alogliptin) But FDA did not see an increase in deaths
associated with alogliptin.
• FDA noted that patients taking saxagliptin have a 27% higher risk of
hospitalization for heart failure compared with those receiving a placebo.

Solving the Challenges ….achieving the balance
41

Sitagliptin Enhances Active Incretin Levels
Through Inhibition of DPP-41–4

Sitagliptin and Metformin Target the
Metabolic Defects of Type 2 Diabetes
45
1. Aschner P et al. Diabetes Care. 2006;29:2632–2637.
2.,Vardarli I et al. Diabetes. 2014;63:663–674.
3. Abbasi F et al. Diabetes Care. 1998;21:1301–1305.
4. Kirpichnikov D et al. Ann Intern Med. 2002;137:25–33.
5. Zhou G et al. J Clin Invest. 2001;108:1167–1174.
6. Solis-Herrera et al. Diabetes Care. 2013;36:2756–2762.
Beta-Cell
Dysfunction
Hepatic Glucose
Overproduction (HGO)
Insulin Resistance
Sitagliptin improves
markers of beta-cell
function and increases
insulin synthesis and
release.1,2
Sitagliptin reduces
HGO through
suppression of
glucagon from alpha
cells.6
Metformin decreases
HGO by targeting the
liver to decrease
gluconeogenesis and
glycogenolysis.4
Metformin has insulin-
sensitizing
properties.3–5
(Liver > Muscle)

Initial Fixed-Dose Combination Therapy With JANUMET™ vs Metformin
Monotherapy: Change from Baseline in HbA1c by Baseline HbA1c at Week
18
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.
HbA1cLSMeanChange
fromBaseline,%
Baseline HbA1c,% <8 ≥8 and <9 ≥9 and <10 ≥10 and <11 ≥11
FAS (Week 18)
P=0.009
P<0.001
P<0.001
Mean HbA1c,% 7.6 8.4 9.5 9.4 10.4 12.2
n=
–1.1
–1.6
–2.0
–2.9
–2.7
–2.1
–1.7
–1.1
–0.8
–4.0
–3.5
–3.0
–2.5
–2.0
–1.5
–1.0
–0.5
0
Sitagliptin/metformin FDC
Metformin
99 95 99 11187 101 124 109 150 148
P=0.158
P=0.111
–3.6

HbA1c-Lowering Efficacy of Sitagliptin at
Week 30 Was Non inferior to That of Glimepiride
in Patients Inadequately Controlled on Metformin1
LS=least squares; SE=standard error.
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.
Week
LSMean(±SE)HbA1c,%
Per-Protocol Population
6.0
6.2
6.4
6.6
6.8
7.0
7.2
7.4
7.6
7.8
8.0
0 6 12 18 24 30
 (95% CI)
0.07% (–0.03, 0.16)
Sitagliptin 100 mg + metformin (n=443)
Glimepiridea + metformin (n=436)
–0.47
–0.54

Sitagliptin Was Associated With a Lower Incidence of
Hypoglycemia and Reduced Body Weight vs Glimepiride1
48
Hypoglycemia Over 30 Weeks Body Weight Change at Week 30
APaT=all patients as treated; CI=confidence interval; LS=least-squares.
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;13:160–168.
2. Data on file, MSD.
PatientsWith≥1
HypoglycemicEpisode,%
LSMean(95%CI)Changein
BodyWeightFromBaseline,kg
n=516 n=518
All patients inadequately controlled on metformin monotherapy (≥1500 mg/day)
(APaT Population)
 (95% CI)
–15.0% (–19.3, –10.9) (P<0.001)
Sitagliptin 100 mg + metformin
Glimepiridea + metformin
 = –2.0 kg
(P<0.001)
n=461
n=465

Observational Study of the Treatment and Follow-up
of Patients With Type 2 Diabetes Receiving Sitagliptin
or Sulfonylurea and Metformin Combination Therapy
49
ODYSSÉE Study
A Real-world Data
SU=sulfonylurea.
1. Valensi P et al. American Diabetes Association 2014. Abstract 136-LB.
2. Data on file. MSD.
2014

ODYSSÉE Study: Results…
Treatment maintenance duration until treatment modification
MetSita group : 43.2 months [95%CI: 41.4 – NE*]
MetSU group : 20.2 months [95%CI: 17.0 - 25.1]
ProportionofPatientsmaintained
*non-evaluable
P.Valensi et al. Treatment Maintenance Duration of Dual Therapy with Metformin and Sitagliptin in Type 2 Diabetes: The Odyssee Observational Study. Diabetes
63(S1): LB-35 Abst 136-LB 2014 Jun 13-17 2014 - ADA 2014 74th American Diabetes Association Scientific Sessions, San Francisco, California Abst: 136-LB

ODYSSÉE: HbA1c Over Time Until
Modification of Combination Therapy1
Sitagliptin + metformin SU + metforminLS=least square; SD=standard deviation; SU=sulfonylurea.
6.4
6.6
6.8
7.0
7.2
7.4
7.6
7.8
Inclusion 6 12 18 24 30 36
LSMeanHbA1c±SD,%
n=1735
n=678
n=1,263
n=490
n=1,089
n=370
n=921
n=286
n=793
n=245
n=688
n=206
n=592
n=190
LS Mean Change in HbA1c:
~ –0.6 in both groups
7.7
7.5
7.3
7.1
6.9
6.7
6.5
Time, months
52
Gliclazide was the most
commonly prescribed SU (54%)

ODYSSÉE: Patient-reported Hypoglycemia
and Change in Weight1,2
53
aDifference between baseline weight was statistically significant: sitaglptin + metformin, 85.0 kg; SU + metformin, 83.4 kg, P=0.002)
SU=sulfonylurea.
100
30
20
10
0
9.7%
21%
PatientsWith≥1EpisodeofHypoglycemia,%
Sitagliptin + metformin (n=1,874) SU + metformin (n=733)
Patient-reported Hypoglycemia
During Study Follow-Up or Until
Change in Therapy
Gliclazide was the most
commonly prescribed SU (54%)

805
57
0
200
400
600
800
1000
Week 104
TotalNumberofEpisodes,(n)
Glipizide Sitagliptin 100 mg/d
*(95% CI) LS Means Change in Body Weight (kg)
in Between Treatment Groups
LS Mean Change in
Body Weight (kg) Over Time
(APaT population)
Overall Number of Episodes
of Hypoglycemia:
Week 0 Through Week 104
Sitagliptin 100 mg/d
(n = 253)
Glipizide
(n = 261)
LSMeanChange
FromBaseline(kg)
0 1224 38 52 78 104
–
2
–
1
0
1
2
Week
∆=−2.3 (−3.0, −1.6)*
Seck et al, Int J Clin Pract 2010
Sitagliptin and Body weight

Sitagliptin and -cell mass
Mu J. et al. Eur J Pharm 2009; 623: 148-154

Week
LSmeanchange
frombaseline±SE
0.05
0.03
0.01
-0.01
-0.03
-0.05
0 24 52
Sitagliptin 100 mg
Glipizide
Per protocol population.
Nauck MA et al. Diabetes Obes Metab 2007;9:194–205.
Data on file, MSD________.
Sitagliptin Lowered and Glipizide
Increased the Proinsulin-to-Insulin Ratio

 Aim: To determine which non-insulin glucose-lowering treatment
regimens are most appropriate in people with type 2 diabetes who choose
to fast during Ramadan.
 Results: A total of 16 studies were included: 9 RCTs and 7 observational
studies. There was evidence that (DPP-4) inhibitors led to fewer
hypoglycaemic events compared with sulphonylureas. Sitagliptin
significantly reduced the number of patients with ≥1 hypoglycaemic
episodes during Ramadan p>0.0001. This was not replicated in the RCTs
of vildagliptin,but a significant reduction was found in the observational
studies p=0.01 with high heterogeneity (I2 =86.7%).
 Conclusions: The analysis supports the use of DPP-4 inhibitors during
Ramadan rather than sulphonylureas for reduction in hypoglycaemia
without a cost to diabetes control and weight
58

59
The safety and effectiveness of non-insulin glucose
lowering agents in the treatment of people with Type 2
Diabetes who observe Ramadan:
A systematic review and meta-analysis

Ongoing or Planned CV randomized controlled clinical trials in
patients with type 2 diabetes & Focus on Heart Failure (HF)
Study
Drug
Trial
acronym
Population
enrollment
(n)
Population
studied
Primary
composite
outcome
HF reported
as
secondary
outcome
Sitagliptin TECOS
14000 Age>50 y +
preexisting CV
disease
CV death
nonfatal MI,
nonfatal stroke
or unstable
angina
Yes
Vildagliptin
---- ---- ---- ---- ----
Saxagliptin
Savor-TIMI
54
16500
Age>40 years
Established CV
disease and/or
multiple risk factor
Cv death , non
fatal MI ,non
fatal ischemic
stroke
yes

Trial Evaluating Cardiovascular
Outcomes with Sitagliptin – TECOS
Overview of Study Design and Selected
Inclusion/Exclusion Criteria

63
is a double-blind randomized, placebo controlled, multi-
national trial in patients with type 2 diabetes coordinated by the Duke
Clinical Research Institute (DCRI) and the university of Oxford Diabetes
Trial Unit (DTU).
It is being conducted in around 40 countries, across Australasia, Asia,
Europe, North America, India and South Africa and commenced in 2008.
aims to compare the impact of adding Sitagliptin as part of
usual care versus usual care without Sitagliptin on Cardiovascular
outcomes. 14,000 patients will be followed for a minimum of 3 years with
the results expected in 2015.

64
aMinimum of 2,000 patients on metformin monotherapy.
bIf eGFR is ≥50 mL/min/1.73 m2, dose of sitagliptin = 100 mg/d; if eGFR is 30 to <50 mL/min/1.73 m2, dose of sitagliptin = 50 mg/d; if eGFR is
<30 mL/min/1.73 m2 during the study, dose reduced to 25 mg/d.
TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; T2DM = type 2 diabetes mellitus; CVD = cardiovascular disease; R = randomization;
AHA = antihyperglycemic agent; HbA1c = hemoglobin A1C; ADA = American Diabetes Association; V = visit; M = month;
T = telephone contact (study participants will also see their usual-care physician regularly); AV = annual visit; eGFR = estimated
glomerular filtration rate.
1. Green JB et al. Am Heart J. 2013;166:983–989.e7.
R
Patients aged ≥50 years with
T2DM, pre-existing CVD, and:
HbA1c 6.5%–8.0%
(48–64 mmol/mol) and dose-
stable for ≥3 months on:
– Metformin, pioglitazone, or
sulfonylurea as
monotherapy or any dual
combination therapya
OR
– Insulin alone or in
combination with
metformin
Sitagliptinb
Placebo
V2
M4
V3
M8 Brief Visit
M18
Brief Visit
M30
Brief Visit
M42
T
M15
T
M21
T
M27
T
M33
T
M39
T
M45
Additional oral AHA agents or insulin added according to usual care
to target HbA1c goals according to current guidelines (eg, ADA)
Continue metformin and/or pioglitazone and/or sulfonylurea,
and/or insulin
Visit 1
Randomization
(Day 1)
End of
Study
VisitAV
M48
AV
M36
AV
M24
AV
M12
TECOS: Summary of Study Design1

65
TECOS: Analysis1
 Primary outcome analysis is designed to demonstrate Non-inferiority
of usual care with sitagliptin vs usual care without sitagliptin for the
primary composite end point of time from randomization to the first
adjudicated:
– CV-related death
– Nonfatal MI
– Nonfatal stroke
– Unstable angina requiring hospitalization
If sitagliptin is found noninferior to placebo, an assessment of
superiority will be performed
TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; MI = myocardial infarction.

66
TECOS: Secondary and Other Prespecified
Outcomes1
 Secondary outcomes
– Composite end point of time to first adjudicateda confirmed CV-related death,
nonfatal MI, nonfatal stroke
– Time to the occurrence of the individual components of the primary end point
– Time to all-cause mortality
– Time to hospital admission for adjudicated congestive heart failure
 Other prespecified outcomes include:
– Changes from baseline in urinary albumin:creatinine ratio, eGFR, HbA1c,
body weight
– Time to initiation of additional antihyperglycemic medications and/or initiation of
chronic insulin
– Counts of outpatient visits and hospitalizations
aCV events will be adjudicated by an independent committee, blinded to study therapy.
TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular; MI = myocardial infarction; eGFR = estimated glomerular filtration
rate.

67
Topline News release :
Merck Announces the Trial Evaluating
Cardiovascular Outcomes with Sitagliptin
(TECOS) Met Primary Endpoint
27th April 2015
 JANUVIA® (sitagliptin), achieved its primary endpoint of non-
inferiority for the composite cardiovascular (CV) endpoint
 Among secondary endpoints, there was no increase in hospitalization
for heart failure in the sitagliptin group versus placebo
 The complete results of TECOS will be presented on June 8, 2015 at
the 75th Scientific Sessions of the American Diabetes Association.

Guidelines & Treatment
Algorithm for
Management of T2DM ?!

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
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)
+
Figure 2. Anti-hyperglycemic therapy
in T2DM: General recommendations Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0
2015

Metformin
high
low risk
neutral/loss
low
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
Metformin
+
Combination
injectable
therapy‡
Insulin (basal)
+
Figure 2. Anti-hyperglycemic therapy
in T2DM: General recommendations Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

Metformin
high
low risk
neutral/loss
low
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
Metformin
+
Combination
injectable
therapy‡
Insulin (basal)
+
Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

Metformin
high
low risk
neutral/loss
low
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-i
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
Metformin
+
Combination
injectable
therapy‡
HbA1c
≥9%
Me ormin
intolerance or
contraindica on
Uncontrolled
hyperglycemia
(catabolic features,
BG ≥300-350 mg/dl,
HbA1c ≥10-12%)
Insulin (basal)
+
or
or
or
Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

Sitagliptin is a different molecule
Sitagliptin
Molecular structure
Half Life (T1/2) 12.4 hrs
DPP-4 Inhibition* post 24 hrs 100mg QD 80-97% @ 24hrs
DPP-4 Peak Inhibition ~97%
Selectivity for DPP-IV vs. DPP-
8/DPP-9*
2600 fold for DPP4 vs. DPP-8
10,000 fold for DPP4 vs. DPP-9
Selectivity High
Metabolism ~16% metabolized
Bioavailability ~87%
Liver Monitoring NO
Elimination
Kidney (87%)
79% mostly unchanged
Liver (13%)
FDA YES
* All use different proprietary assays with different dilutions and therefore % DPP-4 inhibition cannot be compared across assays
F
F
F O
N
NH2
N N
N
CF3
Data on file, MSD

Take home Message……
• Diabetes is a huge and growing problem
• About 50% of T2DM patients are not achieving the A1c goal
• Diabetes is the leading cause to multiple organ-system
complications
• Hypoglycemia , weight gain & B cell function deterioration are
the main challenges during diabetes management

Take home Message……
• Hypoglycemia may be a significant barrier to treatment
adherence
• Sitagliptin / metformin combination is an optimum tool to reach
diabetes goals without compromise on Hypoglycemia nor
weight gain.
• TECOS established cardiovascular safety of Sitagliptin

Ueda2015 diabetes control dr.lobna el-toony

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