ueda2015 diabetes control dr.lobna el-toony

Prof. Lobna El ToonyProfessor 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 40.643.8 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

Hb

A1c

Att

ain

men

t, %

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 RiskN=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 gainWeight gain

and hypoglycaemia

Body w

eig

ht

HbA1c

Pla

sma

glu

cose

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


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 Halbanat 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


• Hypoglycemia

• Weight Gain

• B-Cell exhaustion

• Cardio-vascular safety

Global cardiometabolic risk*

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

History of Diabetes

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-

2559.

ACCORD trial

Results: Cardiovascular

mortality


2559.


2559.

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

StudyDiabetes Duration (mean)

Antihyperglycemic Medicationa

Follow-up(median)

HbA1c: Baseline, Between-arm

DifferenceMicrovascular CVD Mortality

UKPDS1

Newly diagnosed

SU/insulin or metformina vs dietary restriction

10 years7.1% (all patients)b,

–0.9%c ↓ ↔ ↔UKPDS

Long-term follow-up2

10 years post

intervention

No difference in

HbA1c between

treatment armsd↓ ↓ ↓

ADVANCE3 8 yearsIntensive glucose control

including gliclazide vs standard treatment

5 years7.5% (both arms)b,

–0.8%d ↓ ↔ ↔

ACCORD4,5 10 years Multiple drugs in both arms 3.4 years8.1% (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

StudyIntervention

(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

RECORD1Rosiglitazone +

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 CAD7.6%. –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.

Hb

A1

cL

S M

ean

Ch

an

ge

fro

m B

aseli

ne,

%

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 atWeek 30 Was Non inferior to That of Glimepiridein 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

LS

Mean

(±

SE

) H

bA

1c,

%

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.

Pat

ien

ts W

ith

≥1

Hyp

og

lyce

mic

Ep

iso

de,

%

LS

Mea

n (

95%

CI)

Ch

ang

e in

Bo

dy

Wei

gh

t F

rom

Bas

elin

e, k

g

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]

Pro

po

rtio

n o

f P

atie

nts

mai

nta

ined

*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

LS M

ean

HbA

1c±

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%

Pat

ien

t s

Wit

h ≥

1 E

pis

od

e o

f H

ypo

gly

cem

ia, %

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 To

tal N

um

be

r o

f E

pis

od

es

, (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)

LS

Mean

Ch

an

ge

From

Baselin

e (

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

LS

mea

n c

han

ge

fro

m b

asel

ine ±

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

March

2015

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

D I

A N A T

O C

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 TECOS14000 Age>50 y +

preexisting CV

disease

CV death

nonfatal MI,

nonfatal stroke

or unstable

angina

Yes

Vildagliptin---- ---- ---- ---- ----

SaxagliptinSavor-TIMI

5416500

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.

1. Green JB et al. Am Heart J. 2013;166:983–989.e7.

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.

1. Green JB et al. Am Heart J. 2013;166:983–989.e7.

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-i

or

or

or

GLP-1-RA

high low risk

loss

GI

high

GLP-1 receptor agonist

Sulfonylurea

high moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor


loss

GU, dehydration

high

SU

TZD

Insulin§


+

SGLT-2 Inhibitor +

SU

TZD

Insulin§

Metformin +

Metformin +

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono- therapy

Efficacy* Hypo risk

Weight

Side effects

Costs

Dual therapy†

Efficacy* Hypo risk

Weight

Side effects

Costs

Triple therapy

or

or

DPP-4 Inhibitor

+ SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors):

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:

Metformin +

Combination injectable therapy‡

GLP-1-RA Mealtime 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



neutral/loss


low


Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

high low risk

gain

edema, HF, fxs

low

Thiazolidine- dione


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

or

or

or

GLP-1-RA

high low risk

loss

GI

high


Sulfonylurea

high moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor


loss

GU, dehydration

high

SU

TZD

Insulin§


+

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 +



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



neutral/loss


low


Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

high low risk

gain

edema, HF, fxs

low

Thiazolidine- dione


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

or

or

or

GLP-1-RA

high low risk

loss

GI

high


Sulfonylurea

high moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor


loss

GU, dehydration

high

SU

TZD

Insulin§


+

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 +



Insulin (basal)

+

Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0



neutral/loss


low


Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

high low risk

gain

edema, HF, fxs

low

Thiazolidine- dione


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


Sulfonylurea

high moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor


loss

GU, dehydration

high

SU

TZD

Insulin§


+

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 +



HbA1c≥9%

Me orminintoleranceorcontraindica on

Uncontrolledhyperglycemia

(catabolicfeatures,BG≥300-350mg/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 ON

NH2

N NN

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

Thank You

ueda2015 diabetes control dr.lobna el-toony

Documents

diabetes epidemic

diabetes atlas

balance cardiovascular

eurika europe2

hba1c attainment

management of t2dm

traditional oral

growing problem