Overview and rational of main international guiderlines for the treatment of type 2

diabetes

Dr. med. Bernd VossSpecialist in Internal Medicine / Munich, Germany

Regional Director Medical Affairs DiabetesEastern Europe, Middle East, Africa

MSD

Development and Progression of Type 2 Diabetes and Related Complications1,a

2

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.

Insulin levelInsulin level

Insulin resistanceInsulin resistance

Hepatic glucose Hepatic glucose productionproduction

PostprandialPostprandial glucoseglucose

Fasting plasma Fasting plasma glucoseglucose

BBetaeta-cell function-cell function

Progression of Type 2 Diabetes Mellitus

Impaired Glucose Tolerance

Diabetes Diagnosis

Frank Diabetes

4–7 years

Development of Macrovascular Complications

Development of Microvascular Complications

UKPDS: Correlation Between HbA1c and Macro- and Microvascular End Points1

3

Fatal and Nonfatal Myocardial Infarction

0 .5

1

5

0 5 6 7 8 9 10 1 1

14% decrease per 1% decrement in HbA1c

P < 0.0001

Haza

rd R

atio

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.

0.5

1

10

15

0 5 6 7 8 9 10 11

Microvascular End Points

37% decrease per 1% decrement in HbA1c

P < 0.0001

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%*

HbA1C ≥ 6.5%* after trial of lifestyle measures

SUWhere blood glucose control remains or becomes inadequate on metformin

Usual approach Alternatives

SitagliptinWhere insulin is unacceptable

or inappropriate

Insulin (NPH insulin, long-acting insulin

analogues, pre-mix insulin) Monitor use and response and

adjust doses if necessary

ExenatideIf 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

HbA1C ≥ 7.5%*

1

2 +

3 +

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 SUMay 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

inhibitorWhere either a DPP-4 inhibitor or a TZD may be suitable, the choice of treatment should be based

on patient preference

* 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)

DPP-4 inhibitorConsider adding instead of an SU where• Patients are at significant risk of hypoglycaemia

or its consequences• Patients are intolerant of or contra-indicated to SUMay be preferable to TZD where• Further weight gain would cause or exacerbate sign-

ificant problems associated with a high body weight• TZDs are contra-indicated• Previous poor response or intolerance to a TZD

Where either a DPP-4 inhibitor or a TZD may be suitable, the choice of treatment should be based on patient preference

TZD (glitazones)†

Where insulin is unacceptableor inappropriate

MetforminConsider 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

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

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.

HbA1c 6.5%–7.5% b

Monotherapy

MET +

GLP-1 or DPP-4 d

TZD e

Glinide or SU h

TZD + GLP-1 or DPP-4 d

MET +Colesevelam

AGI f

2–3 Months g

2–3 Months g

2–3 Months g

Dual Therapy MET +

GLP-1

or DPP-4 d ± SU j

TZD e

GLP-1

or DPP-4 d ± TZD e

HbA1c >9.0%

No Symptoms

Drug Naive Under Treatment

INSULIN

± Other

Agent(s) k

Symptoms

INSULIN

± Other

Agent(s) k

INSULIN

± Other Agent(s) k

MET +

GLP-1 or

DPP-4 d+

TZD e

Glinide or SU i,j

MET +

GLP-1 or DPP-4 d

or TZD e

SU or Glinide h,i

Triple Therapy

HbA1c 7.6%–9.0%

Dual Therapy l

2–3 Months g

2–3 Months g

Triple Therapy m

INSULIN

± Other Agent(s) k

MET c DPP-4 d GLP-1 TZD e AGI f

MET +

GLP-1

or DPP-4 d+ TZDe

GLP-1

or DPP-4 d + SU j

TZD e

HbA1c Goal≤6.5% a

a May not be appropriate for all patientsb For patients with diabetes and HbA1c <6.5%, pharmacologic Rx

may be consideredc Preferred initial agentd DPP-4 if PPG and FPG or GLP-1 if PPGe TZD if metabolic syndrome and/or NAFLDf AGI if PPGg If HbA1c goal not achieved safelyh Low-dose secretagogue recommendedi Glinide if PPG or SU if FPGj Decrease secretagogue by 50% when added to GLP-1 or DPP-4k a) Discontinue insulin secretagogue with multidose insulin

b) Can use pramlintide with prandial insulinl If HbA1c <8.5%, combination Rx with agents that cause

hypoglycemia should be used with cautionm If HbA1c >8.5%, in patients on dual therapy, insulin should be

considered

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%.

13

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

n=790n=790 n=904n=904

4348

38 37

62

44 41

57

NHANES=National Health and Nutrition Examination Survey.1. Cheung BM, et al. Am J Med. 2009;122:443–453.

37

54

Persistence of Metformin Monotherapy in Patients Not at HbA1c Goal1

15

FPG=fasting plasma glucose.aPatients with type 2 diabetes and HbA1C ≥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 follow-up time = 2.9 years1. Fu AZ et al. Diabetes Obes Metab. 2011;13:765–769.

Prop

ortio

ns o

f Pat

ient

s on

Met

form

in M

onot

hera

py

0.00

1.00

0.75

0.50

0.25

0 1 2 3 4 5Years

Index HbA1C 7% to <8%Index HbA1C 8% to <9%Index HbA1C ≥9%

All patients (Mean HbA1C = 8.0%)

14.0 months

Retrospective analysis using a large US electronic medical record database (N=12,566)a

16

Cardiovascular Complications Are Very Costly Among Patients With Diabetes1

0

3000

6000

9000

12000

15000

18000

21000

1. ADA. Diabetes Care. 2008;31:596–615.

US health care expenditures for chronic complications of diabetes in 2007:US health care expenditures for chronic complications of diabetes in 2007:hospital inpatient expenses based on annual medical claims for 16.3 million peoplehospital inpatient expenses based on annual medical claims for 16.3 million people

$ U

S, m

illio

ns

Neurologic PeripheralVascular

Cardio-vascular

Renal Metabolic Ophthalmic Other

Hypoglycemia Is Associated With Increased Health Care Costs1

17

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 oddsratio 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)

Potential Complications and Effects of Severe Hypoglycemia

18

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

ADVANCE: Severe Hypoglycemia Was Associated With Adverse Clinical End Points and Death1

19

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.

HR (95% CI):3.53 (2.41–5.17)a

HR (95% CI):2.19 (1.40–3.45)a

HR (95% CI):3.27 (2.29–4.65)a

HR (95% CI):3.79 (2.36–6.08)a

HR (95% CI):2.80 (1.64–4.79)a

b b

Non-Severe Hypoglycemic Events WereAssociated With Substantial Loss of Productivity1

20Es

timat

ed P

rodu

ctivi

ty L

oss

Due

toAb

sent

eeism

Fro

m a

n NS

HE, $

a

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.

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 = 279 n = 283 n = 166n = 173 n = 170 n = 88

Significantly More Emergency Department Visits and Hospital Admissions Associated With Hypoglycemia1

21

aIncludes 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.

Emergency department visits Hospital admissions

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Hypoglycemia Other reasons

Any hypoglycemia claima No hypoglycemia claima Any hypoglycemia claima No hypoglycemia claima0.0

0.2

0.4

0.6

0.8

1.0

1.2

Annu

al A

vera

ge

Annu

al A

vera

ge

Hypoglycemia Was Associated With Decreased Health-Related Quality of Life1

22

Without Symptoms With Symptoms WithMild Symptoms

WithModerate Symptoms

WithSevere Symptoms

P<0.0001a

P<0.0001b

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.

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

Hypoglycemia Was Associated With MoreShort-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

Annualized health care expendituresb $3169 $1812 P < 0.01

23

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.bAttributable to 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.

Sweden: Health Care–Related Costs and Hypoglycemia1

24

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.

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.

CostInsulin Users

≤65 YearsInsulin Users

>65 Years

Oral Treatment

Users ≤65 Years

Oral Treatment

Users >65 Years

All Type 2

Diabetes Patients

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

Expected Yearly Cost of Hypoglycemic Events

Abdominal Obesity is Linked to a Higher Risk for MI1

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

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

25

A Brief History of Incretins

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.

1902 – First observation of intestinal effect on pancreatic secretion1,2

1932 – First definition of incretins3

1964 – Demonstration of the incretin effect1,4,5

1966 – First description of DPP-46

1973 – GIP identified as a human incretin1

1986 – Incretin effect shown to be reduced in patients with type 2 diabetes7

1987 – GLP-1 identified as a human incretin8

1995 – DPP-4 identified as an enzyme that inactivates GIP and GLP-19,10

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.

Incretin Hormones Have Key Roles in Glucose Homeostasis

GLP-1

Inhibits gastric emptyinga,1,2

Reduces food intake and body weighta,2

Inhibits glucagon secretion from alpha cells in a glucose-dependent manner1

Stimulates insulin response from beta cells in a glucose-dependent manner1

Is released from L cells in ileum and colon1,2

GIP

Has no significant effects on satiety or body weight2

Does not affect gastric emptying2

Stimulates insulin response from beta cells in a glucose-dependent manner1

Is released from K cells in duodenum1,2

DPP-4 Inhibitors: An Incretin-Based Glucose-Dependent Mechanism for Improving Glycemic Control1–4

28

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.

By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner.

Release ofactive incretinsGLP-1 and GIPa

Blood glucose in fasting and

postprandial states

Ingestion of food

Glucagonfrom alpha cells

(GLP-1)

Hepatic glucose

production

GI tract

DPP-4 enzyme

InactiveGLP-1

XSitagliptin(DPP-4

inhibitor)

Insulin from beta cells

(GLP-1 and GIP)

Glucose-dependent

Glucose-dependent

Pancreas

InactiveGIP

Beta cellsBeta cellsAlpha cellsAlpha cells

Peripheral glucose uptake

Sitagliptin Was Noninferior to Glipizide in Reducing HbA1c at Week 52 (Primary End Point)1

29

Per-Protocol PopulationLS mean change from baseline

at 52 weeks (for both groups): –0.7%

Sulfonylureaa + metformin (n=411 at 52 weeks)

Sitagliptinb + metformin (n=382 at 52 weeks)

Cha

nge

in H

bA1c

Fro

m B

asel

ine

(±SE

), %

Weeks

6.2

6.4

6.6

6.8

7.0

7.2

7.4

7.6

7.8

0 6 12 18 24 30 38 46 52

8.0

8.2

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.

Achieved primary hypothesis of

noninferiority to sulfonylurea

HbA1c Reductions at Week 1041

30

2-Year Per-Protocol Population(Patients Inadequately Controlled on Metformin)

Difference in LS Mean HbA1c= –0.03(95% CI: –0.13, 0.07)

LS M

ean

(95%

CI)

Cha

nge

in H

bA1c

From

Bas

elin

e, %

–0.7

–0.5

–0.3

0

Glipizide + metformin (n=256)

Sitagliptin + metformin (n=248)

Mean baseline HbA1c,% 7.30 7.31

LS=least-squares; SD=standard deviation. 1. Seck T et al. Int J Clin Pract. 2010;64(5):562–576.

Sitagliptin vs Glipizide: Weight Change and Incidence of Hypoglycemia1

31

Pat

ien

ts W

ith

at

Lea

st 1

Ep

iso

de

, %

APaT Population(Patients Inadequately Controlled on Metformin)

Sitagliptin + metformin

Glipizide + metformin

5,3

34,1

0

10

20

30

40

All Patients

Between-groups difference = –28.8% (95% CI: –33.0, –24.5)

n=588 n=584

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.

LS

Mea

n (

±95%

CI)

Bo

dy

We

igh

t C

han

ge

Fro

m B

asel

ine,

kg

Between-groups difference = –2.3 kg(95% CI: –3.0, –1.6)

Hypoglycemia over 104 weeksBody weight at week 104

n=253 n=261

Sitagliptin Was Assoicated With a Lower Risk of Hypoglycemia Compared With Glipizide1

aA hypoglycemic event accompanied by a fingerstick blood glucose measurement of ≤70 mg/dL.bTotal number of events/total number of patients in each subgroup.1. Krobot K et al. Curr Med Res Opin. 2012;28:1–7.

Most recently measured HbA1c value (%)9876

0

.001

.002

.003

.004

.005

Ris

k

Glipizide (age group ≥65 years)

Glipizide (age group <65)

Sitagliptin (age group ≥65 years)

Sitagliptin (age group <65 years)

Confirmed Hypoglycemiaa

n/Nb

316/461

132/123

27/468

4/120

Rationale for Once-Daily Dosing of Sitagliptin Based on DPP-4 Inhibition1

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.

Single-dose study in healthy subjects (n=6)

Hours Postdose0 1 2 4 6 8 12 16 24

DPP-

4 In

hibi

tion,

%a

0

20

40

60

80

100

Sitagliptin 100 mg qd

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

(DPP-8/DPP-4)

48,000 nM

(2600)

1112 ± 50 nM

(210)

244 ± 8 nM

(72)

>100,000 nM

(>10,000)

40,000 nM

(~40,000)

IC50 for DPP-9

(DPP-9/DPP-4)

>100,000 nM

(>5000)

66.2 ± 7.3 nM

(13)

104 ± 7 nM

(31)

>100,000 nM

(>10,000)

>10,000 nM

(>10,000)

IC50 for FAP

(FAP/DPP-4)

>100,000 nM7

(>5000)73,000 ± 8000 nM7 N/A

>100,000 nM

(>10,000)

89 nM

(~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.

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

35

aStudies with results available as of July 2009.1. Williams-Herman D et al. BMC Endocr Disord. 2010;10:7.

Sitagliptin Pooled Safety Analysis: Summary of Adverse Experiences1

Incidence Rate per 100 Patient-Years

Sitagliptin n=5429

Non-exposedn=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)

36

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 non-exposed 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.

Sitagliptin and Metformin Target the Core Metabolic Defects of Type 2 Diabetes

37

Sitagliptin improves measures of (or markers) beta-cell function and increases insulin synthesis and release.1

Sitagliptin reduces HGO through suppression of glucagon from alpha cells.

Metformin decreases HGO by targeting the liver to decrease gluconeogenesis and glycogenolysis.3

Metformin has insulin- sensitizing properties.2–4

(Liver > Muscle, Fat)

Beta-Cell Dysfunction

Hepatic Glucose Overproduction (HGO)

Insulin Resistance

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

Initial Combination Therapy With Sitagliptin Plus Metformin Provided Sustained HbA1c ReductionsThrough 104 Weeks1

38

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.

Sitagliptin 100 mg qd (n=50)Metformin 500 mg bid (n=64) Sitagliptin 50 mg bid + metformin 1000 mg bid (n=105)Metformin 1000 mg bid (n=87)

Sitagliptin 50 mg bid + metformin 500 mg bid (n=96)

ExtensionStudy

24-WeekPhase

ContinuationPhase

LS M

ean

HbA

1c C

hang

e Fr

om B

asel

ine,

%

–1.2

–1.1

–1.3

–1.4

–1.7

Mean baseline HbA1c = 8.5%–8.7%

0 6 12 18 24 30 38 46 54 62 70 78 91 1046.0

6.5

7.0

7.5

8.0

8.5

9.0

Weeks

APT Population (Extension Study)

Sitagliptin Is the Most Widely Prescribed DPP-4 Inhibitor With the Broadest Range of Indications

39

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.

Ongoing Cardiovascular Outcome Trials With DPP-4 Inhibitors

40

TECOS1

Start: Dec 2008Estimated Proj. Completion: Dec 2014N = 14,000

Trial Evaluating Cardiovascular Outcomes With SitagliptinPrimary 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 2009Estimated Proj. Completion: Dec 2014N = 5,400

Examination of Cardiovascular Outcomes: Alogliptin vs. Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary SyndromePrimary 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 2010Estimated Proj. Completion: April 2014N = 16,500

Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus TrialPrimary 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 2010Estimated Proj. Completion: Sept 2018N = 6,000

Cardiovascular Outcome Study of Linagliptin vs. Glimepiride in Patients With Type 2 DiabetesPrimary 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

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

PancreasGut

Nutrient signals

● Glucose

Hormonal signals• GLP-1• GIP

Glucagon(GLP-1)

Insulin (GLP-1,GIP)

Neural signals cells

cells

Complementary Effects of Sitagliptin and Metformin on Incretin Hormone Concentrations in Healthy Adult Subjects1

Total GLP-1 Active GLP-1 Active GIP

Observations in Healthy Subjects Compared With Placeboa

Sitagliptin Increases active GLP-1 and GIP

MetforminNo

effect

Increases total GLP-1 and increases active GLP-1

Does not increase active GIP

Sitagliptin +

Metformin

Additive effect on active GLP-1; increases active GIP

44

GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1.aData observations reported for post-prandial (4hr) weighted mean GLP-1 levels1. Migoya EM. Clin Pharmacol Ther. 2010;88:801–808.2. Data on file, MSD

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

Patients Were Worried About the Risk of Hypoglycemia1

45

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.

Diabcare-Asia 2003 cross-sectional survey of15,549 Asian patients with diabetes (96% type 2, 4% type 1);

answer to the question “I am worried about the risk of hypoglycemic events”R

espo

nden

ts, %

Patients With Type 2 Diabetes and Hypoglycemia WereMore Likely to Have Lower Health-Related Quality of Life1

46

Cross-sectional, internet-based surveya of 2,074 patients with type 2 diabetes who were taking ≥1 oral antidiabetic agent (excluding insulin)

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.

P < 0.0001P < 0.0001

P < 0.0001

P = 0.1627

EQ-5D Domains

P < 0.0001

Adjusted effects of experiencing hypoglycemia symptoms on HRQL

In a Longitudinal Study, a History of Severe Hypoglycemia Was Associated With a Greater Risk of Dementia1

47

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.

Attributable risk of dementia with any hypoglycemia: 2.39% (1.72–3.01)a

n=1,002 n=258 n=205

1.64

4.34 4.28

Earlier and Appropriate Intervention MayImprove Patients’ Chances of Reaching Goal1

Published Conceptual Approach

A1C,

%

Mean A1C of patients

Duration of Diabetes

OAD monotherapy

Diet andexercise

OAD combination

OAD up-titration

OAD + multiple daily

insulininjections

OAD + basal insulin

6

7

8

9

10

Conventional stepwisetreatment approach

Earlier and proactive intervention approach

A1C goal of 7%

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 Prolongationof QT Interval in Patients With Type 2 Diabetes1

49

P=NS

P=0.0003

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.

Euglycemic clamp(n=8)

Hypoglycemic clamp2 weeks after

glibenclamide withdrawal(n=13)

Significant prolongationof QT interval after hypoglycemic clamps– Increased risk of

arrhythmias

0

360

370

380

390

400

410

420

430

440

450

Mea

n Q

T in

terv

al, m

s

Baseline (t=0)

End of clamp (t=150 min)

All patients participated in one hypoglycemic clamp while on treatment with insulin only, and another during combined glibenclamide and insulin therapy.

Hypoglycemic clamp6–8 months after

resuming glibenclamide(n=13)

460 P<0.0001

Severe Hypoglycemia May Cause a Prolongationof QT Interval in Patients With Type 2 Diabetes1

50

P=NS

P=0.0003

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.

Euglycemic clamp(n=8)

Hypoglycemic clamp2 weeks after

glibenclamide withdrawal(n=13)

Significant prolongationof QT interval after hypoglycemic clamps– Increased risk of

arrhythmias

0

360

370

380

390

400

410

420

430

440

450

Mea

n Q

T in

terv

al, m

s

Baseline (t=0)

End of clamp (t=150 min)

All patients participated in one hypoglycemic clamp while on treatment with insulin only, and another during combined glibenclamide and insulin therapy.

Hypoglycemic clamp6–8 months after

resuming glibenclamide(n=13)

460 P<0.0001

Antecedent Hypoglycemia Impaired Markers of Autonomic Function1

51

CVD=cardiovascular disease.1. Adler GK et al. Diabetes. 2009;58:360–366.

Measures of autonomic function in 20 young healthy subjects after antecedent

euglycemic ( ■) or hypoglycemic ( o ) clamp studies.

Sympathetic response tohypotensive stress

Baroreflex sensitivity

0.0

12.5

15.0

17.5

20.0

5.0 2.80

20

30

40

50

60

70

Baseline Post-Nitroprusside

Antecedent ClampGlucose (mmol/L)

Car

diac

Vag

al B

aror

efle

xSe

nsiti

vity

, ms/

mm

Hg

Sym

path

etic

Bur

st F

requ

ency

,bu

rsts

/min

ute

P < 0.04

P < 0.01

Glucose-Dependent Effects of GLP-1 Infusion on Insulinand Glucagon Levels in Patients With Type 2 Diabetes1

52

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.

Glucose

Glucagon When glucose levels approach normal values, glucagon levels rebound.

When glucose levels approach normal values,insulin levels decrease.

*P<0.05Patients with type 2 diabetes (N=10)

mm

ol/L

15.012.510.07.55.0

25020015010050

mg/dL* * * * * * *

pmol

/L

250200150100

50

403020100

mU/L

* ** * * * * *

Infusion

Minutes

pmol

/L

2015105

0 60 120 180 240

* * * *

pmol/L

2015105

PlaceboGLP-1

Insulin

2.50

0

0 0

0

–30

Sitagliptin as Add-on Therapy to Insulin vs Insulin Dose-increase Therapy in Uncontrolled Korean T2DM: Study Design1

56

Randomization Week 24

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)

• BMI 18–35 kg/m2

• HbA1c ≥7.5% and ≤11%

Insulin Increasinga Regimen (n=70)

Sitagliptin Adding Regimen 100 mg qd (n=70)

R

Screening visitWeek –4

Week 12

aSubjects 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

57

1. Hong ES et al. Diabetes Obes Metab. Accepted Article doi: 10.1111/j.1463-1326.2012.01600.x.

Addition of Sitagliptin Significantly Decreased HbA1c Compared to Patients With Insulin Increasing at Week 241

58

HbA

1c, %

Time (weeks)CI=confidence intervalaP < 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.

-0.63%a

(95% CI, -0.93, -0.38)

-0.22%a

(95% CI, -0.55, 0.31)

-0.42%b

(95% CI, -0.91, 0.11)

Significantly More Subjects Adding Sitagliptin Achieved HbA1c ≤ 7%1

59

1. Hong ES et al. Diabetes Obes Metab. Accepted Article doi: 10.1111/j.1463-1326.2012.01600.x.

All Subjects

P=0.021

Prop

ortio

n of

Sub

ject

s A

chie

ving

HbA

1c ≤

7%

, %

Addition of Sitagliptin Was Associated With a Lower Incidence of Hypoglycemia and Reduced Body Weight vs the Insulin Increasing Regimen1

60

Body Weight Change at Week 24

1. Hong ES et al. Diabetes Obes Metab. Accepted Article doi: 10.1111/j.1463-1326.2012.01600.x.

Cha

nge

in B

ody

Wei

ght F

rom

Bas

elin

e, k

g

Sitagliptin Add-on

Insulin Increasing

= –1.8 kg (P <0.05)

Hypoglycemia Over 24 Weeks

Patie

nts

With

≥1

Hyp

ogly

cem

ic E

piso

de, %

P <0.05

P <0.05

Sitagliptin Add-on

Insulin Increasing

Mean Daily Insulin Use Increased Significantly in the Insulin Increasing Patients1

61

aP<0.05 for 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 Week 0 Week 24

Mea

n In

sulin

Use

(U/d

ay)

25% increase from baseline

-2.5 (95% CI, -4.5, -1.3) 10.1 (95% CI, 4.5, 14.9)

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

62

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.

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

63

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

Adverse ExperienceSitagliptin

n=5,429Non-exposed

n=4,817Between-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)

64

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.

Sitagliptin Pooled Safety Analysis: No Difference in MACEa Between Sitagliptin and Non-exposed Groups1

Adverse Experience

Incidence Rate per 100 Patient-Years

Sitagliptin n=5429

Non-exposedn=4817

Between-Groups Difference (95% CI)b

Relative Risk Ratio (95% CI)

MACE 0.6 0.9 –0.3 (–0.7, 0.1) 0.68 (0.41, 1.12)

66

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.

Chemical Class

β-Phenethylamines1 Cyanopyrrolidines Aminopiperidine8 Xanthine

Generic Name

Sitagliptin2,3 Vildagliptin2,4,5 Saxagliptin2,6,7 Alogliptin9,10 Linagliptin11,12

Molecular Structure

DPP-4 Inhibitory Activity (IC50)

9.96 ± 1.03 nM 5.28 ± 1.04 nM 3.37 ± 0.90 nM 6.9 ± 1.5 nM ~1 nM

Half-life 12.4 h ~2–3 h2.5 h (parent)

3.1 h (metabolite)12.4–21.4 h 113–131 h

DPP-4 Inhibitors Differ in Molecular Structures and Pharmacologic Properties

DPP-4=dipeptidyl peptidase-4. IC50 =half maximal inhibitory concentration1. 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.

F

F

F O

N

NH2

N NN

CF3

N N

OH3C

O N

CN

NH2

N

O

HH

NCHO

NH2

HO

NH

O

N

NC

N

NO

N

N

N

NN

O

NH2

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 h2.5 h (parent)

3.1 h (metabolite)12.4–21.4 h(25–800 mg)

113–131 h(1–10 mg)

Distribution 38% protein bound 9.3% protein bound Low protein binding N/A

Prominent concentration-

dependent protein binding:

<1 nM: ~99%>100 nM: 70%–80%

Metabolism ~16% metabolized69% metabolized

mainly renal(inactive metabolite)

Hepatic (active metabolite)

CYP3A4/5 <8% metabolized ~26% metabolized

EliminationRenal 87%

(79% unchanged)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)

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

Conclusion: Inhibition of DPP-8 and/or DPP-9 resulted in multiorgan toxicities in rats and dogs.

2-Week Rat Study at 10, 30 100 mg/kg/day; Acute dog toxicity at 10 mg/kg

DPP=dipeptidyl peptidase; QPP=quiescent cell proline dipeptidase.1. Lankas GK et al. Diabetes. 2005;54:2988–2994.

Selectivity:Comparative Toxicity Studies1

2-Week Rat Toxicity Nonselective QPP SelectiveDPP-8/9

SelectiveDPP-4

Selective

Alopecia Thrombocytopenia Anemia Enlarged spleen Mortality

Acute Dog Toxicity

Bloody diarrhea

Saxagliptin Was Noninferior to Sitagliptin in Reducing HbA1c at 18 Weeks1

71

Primary End Point (Per-Protocol Population; on background of metformin therapy)

Mean baseline HbA1c, %

Cha

nge

From

Bas

elin

e in

A

djus

ted

Mea

n H

bA1c

(SE)

, %

0.09 (95% CI: –0.01, 0.20)a

(Prespecified noninferiority margin=0.30%)

Sitagliptin 100 mg + metformin

Saxagliptin 5 mg + metformin

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)

7.69 7.68

–0.62(95% CI: –0.69, –0.54)

–0.52(95% CI: –0.60, –0.45)

–0.60

–0.45

–0.30

–0.15

0.00

–0.75

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.

n=343 n=334

FPG Reductions With Sitagliptin vs. Saxagliptin at 18 Weeks1

72

Secondary End Point (FAS Population; on background of metformin therapy)FP

G L

S M

ean

(±SE

) Cha

nge

From

Bas

elin

e, m

mol

/L

–0.90

–0.60

–1.2

–0.9

–0.6

–0.3

0Mean baseline FPG, mmol/L 8.89 8.86

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+ metforminSaxagliptin 5 mg + metformin

n=392 n=397

0.30 (95% CI: 0.08, 0.53)a

OPTIMA : Optimized Glycemic Control With Vildagliptin vs. Sitagliptin - Study Design1

CGM=continuous glucose monitoring.1. Guerci B et al. French Diabetes Society (SFD) Congress. Nice, France. 2012. Poster 299.

R

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

8 Weeks

Vildagliptin + Metformin (N=19)

Sitagliptin + Metformin (N=19)

CGM for 3 days

CGM for 3 days

CGM for 3 days

2-4 Weeks

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

74

1. Guerci B et al. French Diabetes Society (SFD) Congress. Nice, France. 2012. Poster 299.

OPTIMA : Glycemic Variability Results Were Similar Between Sitagliptin and Vildagliptin Treated Groups1

75

At baselineAt 8 weeks

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.

SD of 24-h Mean Glycemia

MAGE

Varia

ble,

mg/

dL

MODD

P=0.61

P=0.83

P=0.89