Slide Source: Lipids Online Slide Library New Approaches to Achieving Good Glycemic Control in Type 2 Diabetes: Part 1

Slide Source:Lipids Online Slide Librarywww.lipidsonline.org

New Approaches to Achieving New Approaches to Achieving Good Glycemic Control in Type 2 Good Glycemic Control in Type 2 Diabetes: Diabetes: Part 1Part 1


Challenges and Solutions :

Too many patients! – Prevention strategies can work

Failure to attain and sustain optimal long-term glycemic control

Hypoglycemia – major limitation to intensive therapy

Inadequate postprandial glucose control

Unpredictable glucose fluctuations

Weight gain – new treatments lead to weight loss

Excess cardiovascular disease and events

Attempting normoglycemia led to increased mortality

Not enough comparative effectiveness studies that are long term – UKPDS and ADOPT demonstrated differences between drugs in the long term

Despite Important Advances in Therapy, Despite Important Advances in Therapy, Glycemic Control Is Not OptimalGlycemic Control Is Not Optimal


Unmet ChallengesUnmet Challenges

Attaining standards of care– Identifying most effective sequence and

combination of therapies

Linking effective diabetes therapies with:– Long-term (durable) glucose control– Proven micro- and macrovascular protection– No side effects such as weight gain and

hypoglycemia– Patient friendliness and not increasing burden

Developing novel therapies based on pathophysiological defects


Pathogenesis Concepts in Type 2 Pathogenesis Concepts in Type 2 DiabetesDiabetes Insulin resistance occurs early, before glucose

intolerance– Genetic cause?– Environmental: obesity, aging, lifestyle, etc.

Healthy cells compensate and remain euglycemic

“Susceptible” cells (in predisposed individuals) -cell dysfunction results in imperfect

compensation– Progress to prediabetes stage– Onset of acquired abnormalities leads to worse

hyperglycemia=glucotoxicity (a vicious cycle)


Pathogenesis of Type 2 DiabetesPathogenesis of Type 2 Diabetes

HyperglycemiaHyperglycemiaHyperglycemiaHyperglycemia

LiverLiver

Increased GlucoseIncreased GlucoseProduction Production

Reprinted with permission from DeFronzo RA. Diabetes. 1988;37:667-687. Copyright © 1998 American Diabetes Association. All rights reserved.

Impaired Insulin Impaired Insulin SecretionSecretion

PancreasPancreas

LiverLiver

Decreased Decreased Glucose UptakeGlucose Uptake

MuscleMuscle


75

100

125

150

Pancreatic Islet Dysfunction Leads to Insufficient Pancreatic Islet Dysfunction Leads to Insufficient Insulin and Elevated Glucagon in Type 2 DiabetesInsulin and Elevated Glucagon in Type 2 Diabetes

Reprinted with permission from Müller WA et al. N Engl J Med. 1970;283:109-115. Copyright © 1970 Massachusetts Medical Society. All rights reserved.

pg

/mL

CHO = high-carbohydrate; NGT = normal glucose tolerance; TD2 = type 2 diabetes

Time (min)

0 60 120 180 240-60

GlucagonGlucagon

0

50

100

150

uU

/mL

InsulinInsulin

GlucoseGlucose

T2D

NGT

T2D

NGT

0100

200

300

400CHO meal

mg/d

L T2D

NGT


Reprinted with permission from DeFronzo R et al. Reprinted with permission from DeFronzo R et al. DiabetesDiabetes. 2009;58:773-795. . 2009;58:773-795. Copyright © 2009 American Diabetes Association. All rights reserved.Copyright © 2009 American Diabetes Association. All rights reserved.

Ominous OctetOminous Octet

In c re a s e dH G P

H y p e rg ly c e m ia

E T IO L O G Y O F T 2 D M

D E F N 7 5 -3 /9 9 D e c re a s e d G lu c o s eU p ta k e

Im p a ire d In s u linS e c re tio n In c re a s e d L ip o ly s is

DecreasedDecreasedIncretin EffectIncretin Effect

Decreased InsulinDecreased InsulinSecretionSecretion

IncreasedIncreasedHepatic GlucoseHepatic Glucose

ProductionProduction

Islet– cell

IncreasedIncreasedGlucagonGlucagonSecretionSecretion

Decreased Decreased Glucose UptakeGlucose Uptake

Increased Increased LipolysisLipolysis

IncreasedIncreasedGlucoseGlucose

ReabsorptionReabsorption

HYPERGLYCEMIAHYPERGLYCEMIA

NeurotransmitterNeurotransmitterDysfunctionDysfunction


Agent Examples Mechanism Action

SUsSUs glyburide, glipizide, glimepiride

Closes KATP channels Pancreatic insulin secretion

‘‘GlinidesGlinides repaglinide, nateglinide

Closes KATP channels Pancreatic insulin secretion

BiguanidesBiguanides metformin Activates AMP-kinase Hepatic glucose production

TZDsTZDs rosiglitazone, pioglitazone

Activates PPAR- Peripheral insulin sensitivity

-GIs-GIs acarbose, miglitol Blocks small bowel-glucosidase

Intestinal carbohydrate absorption

GLP-1 R GLP-1 R agonistsagonists

exenatide, liraglutide

Activates GLP-1 receptors

Pancreatic insulin secretion; glucagon secretion; delays gastric emptying; satiety

Amylino-Amylino-mimeticsmimetics

pramlintide Activates amylin receptors

Pancreatic glucagon secretion; delays gastric emptying; satiety

DPP-4 DPP-4 inhibitorsinhibitors

sitagliptin, saxagliptin

Inhibits DPP-4, endogenous incretins

Pancreatic insulin secretion; pancreatic glucagon secretion

Bile acid Bile acid sequestrantssequestrants

colesevelam Binds bile acid cholesterol

?

D2 agonistsD2 agonists bromocriptine Activates dopaminergic receptors

‘Resets hypothalamic circadian organization’; insulin sensitivity

T2DM: Therapeutic Landscape (Noninsulin) 2012T2DM: Therapeutic Landscape (Noninsulin) 2012

Inzucchi SE et al. Diabetes Care 2012;35:1364-1379.


Agent A1c Advantages Disadvantages Cost

SUsSUs 1–2% Microvasc risk Hypo, wt gain, -cell exhaust

$

‘‘GlinidesGlinides 1–1.5% PPG Hypo, wt gain, -cell exhaust, dose frequency

$ $ $

BiguanidesBiguanides 1–2% Wt loss, no hypo, CVD, ? malignancy

GI, lactic acidosis B12-deficiency

$

TZDsTZDs 1–1.5% No hypo; -cell preservTG HDL BP ? CVD (pio)

Wt gain, edema / HF Bone fxs, ? CVD (rosi)

$ $ $

-GIs-GIs 0.5–1% PPG, ? CVD; GI, dose frequency $ $

GLP-1 R GLP-1 R agonistsagonists

1% Wt loss,? -cell preserv, ? CV benefits

GI; ? pancreatitis, injections

$ $ $

Amylino-Amylino-mimeticsmimetics

0.5% Wt loss, PPG GI, dose frequency, injections

$ $ $

DPP-4 DPP-4 inhibitorsinhibitors

0.6–0.8% No hypo Urticaria / Angioedema; ? pancreatitis

$ $ $

Bile acid Bile acid sequestrantssequestrants

0.5% No hypo; LDL-C GI; TGs $ $ $

D2 agonistsD2 agonists 0.5% No hypo Nausea; dizziness $ $ $

T2DM: Therapeutic Landscape (Noninsulin) 2012T2DM: Therapeutic Landscape (Noninsulin) 2012

Inzucchi SE et al. Diabetes Care 2012;35:1364-1379.


Prevention of Type 2 DiabetesPrevention of Type 2 DiabetesStudy Subjects Intervention Relative Risk Reduction

Da Quing1 IGT Diet or Exercise or Both 42% / 49% / 34%

Finnish DPS2 IGT Lifestyle 58%

DPP3 IGT Lifestyle 58%

DPP3 IGT /“IFG” Metformin 31%

STOP-NIDDM4 IGT Acarbose 25%

EDIP5 IFG Acarbose NS

XENDOS6 IGT Orlistat 45%

TRIPOD7 Prior GDM Troglitazone 55%

DREAM8,9 IFG Rosiglitazone / Ramipril 62% / NS

ACT NOW10 IGT Pioglitazone 72%

ORIGIN11 IGT / “IFG” Insulin Glargine / Omega-3

1Li G et al. Lancet. 2008;371:1783-1789 | 2Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350 | 3Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403 | 4Chiasson JL et al. Lancet. 2002;359:2072-2077| 5Kirkman MS et al. Diabetes Care. 2006;29:2095-2101 | 6Torgerson JS et al. Diabetes Care. 2004;27:155-161 | 8DREAM Trial Investigators. Lancet. 2006;368;1096-1105 | 9DREAM Trial Investigators. N Engl J Med. 2006;355:1551-1562 | 10DeFronzo RA et al. N Engl J Med. 2011;364:1104-1115 | 11ORIGIN Trial Investigators. Am Heart J. 2008;155:26-32.

IFG: impaired fasting glucoseIGT: impaired glucose toleranceGDM: gestational diabetes mellitusNS: not significant

Med

icati

on

Behavio

r


Screening and Diagnosis ofScreening and Diagnosis ofDisorders of Glucose MetabolismDisorders of Glucose Metabolism

• IFG: fasting (8 hours) plasma glucose 100–125 mg/dL• IGT: 2-hour value in 75-g OGTT 140–199 mg/dL• Diabetes: FPG ≥ 126 mg/dL or 2-hour OGTT ≥ 200 mg/dL; should be confirmed on a separate

day

IFG or IGTIFG or IGTIFG or IGTIFG or IGT IFG and IGTIFG and IGT+ Other Features*+ Other Features*

IFG and IGTIFG and IGT+ Other Features*+ Other Features* DiabetesDiabetesDiabetesDiabetes

Screen for Diabetes:Screen for Diabetes:Fasting plasma glucose orFasting plasma glucose or2-hour, 75-g oral glucose 2-hour, 75-g oral glucose

tolerance testtolerance test

Screen for Diabetes:Screen for Diabetes:Fasting plasma glucose orFasting plasma glucose or2-hour, 75-g oral glucose 2-hour, 75-g oral glucose

tolerance testtolerance test

Lifestyle InterventionLifestyle InterventionLifestyle InterventionLifestyle Intervention Lifestyle InterventionLifestyle Interventionand / or Metforminand / or Metformin

Lifestyle InterventionLifestyle Interventionand / or Metforminand / or Metformin

Lifestyle InterventionLifestyle Intervention+ Metformin+ Metformin

Lifestyle InterventionLifestyle Intervention+ Metformin+ Metformin

*<60 years of age, reduced HDL-C, BMI ≥35 kg/m2, hypertension, elevated triglycerides, A1C >6.0%, family history of diabetes in first-degree relative

IFG=impaired fasting glucose; IGT=impaired glucose tolerance


The ABCs of Diabetes CareThe ABCs of Diabetes Care

A1C– American Diabetes Association (ADA) recommends A1C <7.5%

= average glucose of 150 mg/dL– American Association of Clinical Endocrinologists (AACE) /

International Diabetes Federation (IDF) recommend A1C <6.5% = average glucose of 135 mg/dL

Blood pressure– <130/80 mm Hg

Cholesterol– LDL-C: <100 mg/dL (<70 mg/dL in very high-risk patients)– HDL-C: >40 mg/dL in men and >50 mg/dL in women– Non-HDL-C: <130 mg/dL (100 mg/dL in high-risk patients)– TG: <150 mg/dL

Don’t forget aspirin!

American Diabetes Association. Diabetes Care. 2005;28:S4-S36 |International Diabetes Federation. Diabetic Med. 1999;16:716-730.


ACCORD Study Group. N Engl J Med. 2008;358:2545-2559 | ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572.

10,251 participants

Mean age: 62 years

Median duration of diabetes

mellitus: 10 years

Mean A1C at entry: 8.3%

Known heart disease or

at least 2 risk factors

10,251 participants

Mean age: 62 years

Median duration of diabetes

mellitus: 10 years


Known heart disease or

at least 2 risk factors

Standard

A1C 7.0%–7.9%

Standard

A1C 7.0%–7.9%

ACCORDACCORD ADVANCEADVANCE

Intensive

A1C <6.0%

Intensive

A1C <6.0%

CONCLUSION: Intensive glucose-lowering did not significantly reduce CVD events (primary outcome) may cause harm in high-risk patients with type 2 diabetes (increased mortaltiy).

CONCLUSION: Intensive glucose-lowering did not significantly reduce CVD events (primary outcome) may cause harm in high-risk patients with type 2 diabetes (increased mortaltiy).

11,140 participants

Mean age: 66 years

Mean duration of diabetes

mellitus: 8 years


History of major CV event

or at least 1 risk factor

11,140 participants

Mean age: 66 years

Mean duration of diabetes

mellitus: 8 years


History of major CV event

or at least 1 risk factor

Standard

A1C usual care

Standard

A1C usual careIntensive

A1C ≤6.5%

Intensive

A1C ≤6.5%

CONCLUSION: Intensive glucose-lowering did not significantly reduce CVD events (primary outcome) reduces renal complications in high-risk patients by 21% (95% CI, 7–34%) and did not increase mortality

CONCLUSION: Intensive glucose-lowering did not significantly reduce CVD events (primary outcome) reduces renal complications in high-risk patients by 21% (95% CI, 7–34%) and did not increase mortality

Main Findings from the ACCORD and Main Findings from the ACCORD and ADVANCE StudiesADVANCE Studies


A1C <7.0% Is Appropriate for Most A1C <7.0% Is Appropriate for Most Patients with DiabetesPatients with Diabetes

An A1C value of <7.0% is appropriate and well supported by clinical trial results:– There are no data to support an A1C goal of <7.0% for reducing

cardiovascular risk

For individual patients, intensifying the regimen should be weighed by the potential risks and benefits:– History of severe hypoglycemia– Limited life expectancy– Children – Comorbid conditions– Longstanding diabetes and minimal or stable microvascular

complications

Inzucchi SE et al. Diabetes Care 2012;35:1364-1379. | American Diabetes Association. Diabetes Care. 2008;31:S12-S54.


[Insert Title Here].ppt

ACCORD, ADVANCE: Long-Term Glycemic ACCORD, ADVANCE: Long-Term Glycemic Control in High-Risk T2DMControl in High-Risk T2DM

Glycemic control reduces microvascular events

Intensive glucose lowering does not lower major cardiovascular events compared to standard glucose lowering – Antihypertensive, lipid-lowering, and antiplatelet therapies

remain standards of pharmacologic care to reduce cardiovascular events

Lacking consensus for:– Optimal glucose targets for long-term control – Preferred regimen to maintain control

T2DM = type 2 diabetes mellitus

ACCORD Study Group. N Engl J Med. 2008;358:2545-2559 | ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572.


Reprinted from Holman RR et al. N Engl J Med. 2008;359:1577-1589. Copyright © 2008 Massachusetts Medical Society. All rights reserved.

0.0

0.2

0.4

0.6

0.8

1.0

Pro

port

ion w

ith E

ven

t

Years Since Randomization

P=0.01P=0.01

No. at RiskConventional TherapySulfonylurea–insulin

11382729

10132488

8572097

5781459

221577

2066

UKPDS Kaplan–Meier Curves for Prespecified UKPDS Kaplan–Meier Curves for Prespecified Aggregate Clinical Outcome: Aggregate Clinical Outcome: Myocardial InfarctionMyocardial Infarction

10 15 20 250 5

Conventional Conventional TherapyTherapy

Sulfonylurea–insulinSulfonylurea–insulin


Reprinted from Holman RR et al. N Engl J Med. 2008;359:1577-1589. Copyright © 2008 Massachusetts Medical Society. All rights reserved.

0.0

0.2

0.4

0.6

0.8

1.0

Pro

port

ion w

ith E

ven

t

Years Since Randomization

P=0.005P=0.005

No. at RiskConventional TherapyMetformin

411342

360317

311274

213214

95106

416

UKPDS Kaplan-Meier Curves for a Prespecified UKPDS Kaplan-Meier Curves for a Prespecified Aggregate Clinical Outcome: Aggregate Clinical Outcome: Myocardial InfarctionMyocardial Infarction

10 15 20 250 5

Conventional Conventional TherapyTherapy

MetforminMetformin


Most Intensive Less Intensive Least Intensive

Patient AgePatient Age

Disease DurationDisease Duration

40 45 50 55 60 65 70 75

5 10 15 20

Other ComorbiditiesOther Comorbidities

None Few/Mild Multiple/Severe

Hypoglycemia RiskHypoglycemia Risk

Low HighModerate

8.0%8.0%6.0%6.0% 7.0%7.0%

Established Vascular ComplicationsEstablished Vascular Complications

None Early Microvascular Advanced Microvascular

Psychosocioeconomic ConsiderationsPsychosocioeconomic Considerations

Highly Motivated, Adherent, Knowledgeable, Excellent

Self-Care Capacities, Comprehensive Support Systems

Less Motivated, Nonadherent, Limited Insight, Poor

Self-Care Capacities, Weak Support Systems

Cardiovascular

Reprinted with permission from Ismail-Beigi F et al. Ann Intern Med 2011;154: 554-559. Copyright © 2011 American College of Physicians. All rights reserved.

Individualizing A1C Targets in Type 2 DiabetesIndividualizing A1C Targets in Type 2 Diabetes


Therapy for Type 2 Diabetes: Therapy for Type 2 Diabetes: Sites of ActionSites of Action

Saltiel AR, Olefsky JM. Diabetes. 1996;45:1661–1669 |Drucker DJ. Mol Endocrinol. 2003;17:161–171.

Alpha-glucosidase inhibitorsAlpha-glucosidase inhibitors

IncretinsIncretins Insulin secretionInsulin secretion

Glucagon secretionGlucagon secretion

InhibitInhibitcarbohydratecarbohydratebreakdownbreakdown

IncretinsIncretins

Slow gastric emptyingSlow gastric emptying

SecretagoguesSecretagoguesSimulate insulin Simulate insulin

secretionsecretion

ThiazolidinedionesThiazolidinediones Glucose intakeGlucose intake

FFA outputFFA output

MetforminMetforminThiazolidinedionesThiazolidinediones Glucose metabolismGlucose metabolism

MetforminMetforminThiazolidinedionesThiazolidinediones

Suppress glucose productionSuppress glucose production


Initial drug monotherapy

ADA/EASD Position StatementADA/EASD Position Statement

Reprinted with permission from Inzucchi SE et al. Diabetes Care. 2012;35:1364-1379. Copyright © 2012 American Diabetes Association. All rights reserved.

Combination therapy: 2 drugs

Efficacy (A1C)HypoglycemiaWeightSide effectsCosts

More-complex insulin strategies

Combination therapy: 3 drugs

Efficacy (A1C)HypoglycemiaWeightSide effectsCosts


160

150

140

130

120

ADOPT: ADOPT: AA DDiabetes iabetes OOutcome utcome PProgression rogression TTrialrial

Reprinted with permission from Kahn SE et al. N Engl J Med. 2006;355:2427-2443.Copyright © 2006 Massachusetts Medical Society. All rights reserved.

0

1

Fast

ing

Pla

sma G

luco

se

(mg/d

l)

Time (years)0 1 2 3 4 5

Rosiglitazone Sustained Fasting Plasma Glucose Over Time

0

3408 3054 2647 2242 840Number of patients: 4118

SU

MET

RSG

Treatment Difference at 4 Years

RSG VS MET -9.8 (-12.7 to -7.0), P<.001

RSG VS SU -17.4 (-20.4 to -14.5), P<.001


Expectations for New Agents Expectations for New Agents and/or New Strategiesand/or New Strategies

Modify disease progression and halting the decline in -cell function – better long-term control

Reducing cardiovascular morbidity and mortality

Lowering A1C to targets as close to normal as possible without unacceptable hypoglycemia in selected populations

Lowering A1C with no weight gain or lowering A1C with weight loss (ideally)

No unexpected side effects in the long term (eg rosiglitazone)


Incretin Hormones in Incretin Hormones in Type 2 DiabetesType 2 Diabetes


IncretinsIncretins

Gut-derived hormones, secreted in response to nutrient ingestion, that potentiate insulin secretion from islet cells in a glucose-dependent fashion, and lower glucagon secretion from islet cells

Two predominant incretins:– Glucagon-like peptide–1 (GLP-1)– Glucose-dependent insulinotropic peptide (GIP)

(also known as gastric inhibitory peptide)

Incretin effect is impaired in type 2 diabetes– Known as GLP-1 deficiency


The Incretin Effect: Insulin Secretion Is The Incretin Effect: Insulin Secretion Is Greater in Response to Oral vs IV GlucoseGreater in Response to Oral vs IV Glucose

0

50

100

150

200

-30 0 30 60 90 120 150 180 210

Time (min)

Glu

cose

(m

g/d

L)

Insu

lin (

pm

ol/L)

0

100

200

300

400

-30 0 30 60 90 120 150 180 210

Time (min)

Oral

IV

Nauck M et al. J Clin Endocrinol Metab. 1986;63:492-498.

Effect diminished in diabetesEffect diminished in diabetes


Role of Incretins in Glucose HomeostatisRole of Incretins in Glucose Homeostatis

DPP-4=dipeptidyl peptidase–4GIP=glucose-dependent insulinotropic peptideGLP-1=glucagon-like peptide–1

Beta cellsAlpha cellsBeta cellsAlpha cells

InactiveInactiveGLP-1GLP-1

Blood Blood Glucose Glucose

Blood Blood Glucose Glucose

GI tractGI tract

Release of gut Release of gut hormones –hormones –

IncretinsIncretins

Ingestion of foodIngestion of food

Glucose Glucose uptake by uptake by

muscles muscles

Glucose Glucose uptake by uptake by

muscles muscles

Glucose Glucose production production

by liver by liver

Glucose Glucose production production

by liver by liver

InactiveInactiveGIPGIP

DPP-4DPP-4enzymeenzyme

Glucose Glucose dependent dependent glucagon from glucagon from alpha cells alpha cells (GLP-1)(GLP-1)

Glucose-Glucose-dependent dependent insulin from insulin from beta cells beta cells (GLP-1, GIP)(GLP-1, GIP)

ActiveActiveGLP-1 & GIPGLP-1 & GIP

PancreasPancreas


Metabolism of Metabolism of Glucagon-Like Peptide–1Glucagon-Like Peptide–1 and and Glucose-Dependent Insulinotropic PeptideGlucose-Dependent Insulinotropic Peptide

DPP-4

CapillaryCapillary

Dipeptidyl peptidase–4 (DPP-4)– Ubiquitous, specific protease– Cleaves N-terminal dipeptide– Inactivates >50% of GLP-1 ~1 min

>50% of GIP in ~7 min

Active HormonesActive Hormones

GLP-1 [7-36NHGLP-1 [7-36NH22]]

GIP [1-42]GIP [1-42]

Inactive MetabolitesInactive Metabolites

GLP-1 [9-36NHGLP-1 [9-36NH22]]

GIP [3-42]GIP [3-42]

GIP = glucose-dependent insulinotropic peptide; GLP-1 = glucagon-like peptide-1


Glucagon-Like Peptide–1 (GLP-1) IncreasesGlucagon-Like Peptide–1 (GLP-1) Increases-Cell Response and Decreases -Cell Response and Decreases -Cell Workload-Cell Workload

Larsson H et al. Acta Physiol Scand .1997;160:413-422 | Drucker DJ. Diabetes. 1998;47:159-169.

Stomach:Stomach: Helps regulate Helps regulate

gastric emptyinggastric emptying

-Cell -Cell workloadworkload

-Cell -Cell responseresponse

-Cells:-Cells: Enhance glucose- Enhance glucose-dependent insulin dependent insulin

secretionsecretion

GLP-1 secreted GLP-1 secreted upon the ingestion upon the ingestion

of foodof food

GLP-1 secreted GLP-1 secreted upon the ingestion upon the ingestion

of foodof food

-Cells:-Cells: Postprandial Postprandial

glucose secretionglucose secretion

Promotes satiety and Promotes satiety and reduces appetitereduces appetite

Liver:Liver: Glucagon reduces Glucagon reduces

hepatic glucose hepatic glucose outputoutput


Glucagon-Like Peptide–1 Actions Are Glucose Glucagon-Like Peptide–1 Actions Are Glucose Dependent in Patients with Type 2 DiabetesDependent in Patients with Type 2 Diabetes

Nauck NA et al. Diabetologia. 1993;36:741-744.

Glucagon-like peptide–1 (GLP-1; 7–36 amide) 1.2 pmol/kg/min or placebo was infused intravenously in 10 fasting patients with type 2 diabetes not controlled with diet and sulfonylurea therapy ± metformin or acarbose (mean A1C 11.6%, mean plasma glucose 13.1 mmol/l)

With GLP-1 treatment– Insulin and C-peptide increased significantly from

baseline in all patients– Glucagon decreased significantly– Plasma glucose was reduced to normal fasting

concentrations (mean 4.9 mmol/l) within 4 hours– Once normalized, plasma glucose was not further Once normalized, plasma glucose was not further

reduced despite ongoing GLP-1 infusionreduced despite ongoing GLP-1 infusion


Glucagon-Like Peptide–1Glucagon-Like Peptide–1 Normalizes Normalizes Postprandial Hyperglycemia in Patients Postprandial Hyperglycemia in Patients with Type 2 Diabeteswith Type 2 Diabetes

Nauck MA et al. Acta Diabetol. 1998;35:117-129.

Time (h)

Pla

sma g

luco

se (

mg/d

l)

0

300

100

50

150

200

250

2 3 4 1 0 –1

Infusion

GLP-1 [7-36 amide] 1.2 pmol/kg/min

Placebo

Liquid meal

0

300

100

50

150

200

250

2 3 4 1 0 –1

Infusion

GLP-1 [7-36 amide] 1.2 pmol/kg/min

Placebo

Liquid meal

Pla

sma g

luco

se (

mg/d

l)

Healthy subjects T2DM patients

Time (h)


Continuous Continuous Glucagon-Like Peptide–1Glucagon-Like Peptide–1 Infusion Reduces Appetite over 6 WeeksInfusion Reduces Appetite over 6 Weeks

All data for patients treated with glucagon-like peptide–1 (n = 10).No changes in these parameters were observed in the saline group.

0

100

200

300

400

500

Mean (SE) AUC for Visual

Analogue Score (mm) vs Time (h)

Time (wk)

610

Zander M et al. Lancet. 2002;359:824–830.

Time (wk)

*Prospective food intake

*Hunger

*Satiety

*Fullness

*p<.05


Incretin-Based Therapies Approved or Incretin-Based Therapies Approved or in Late-Stage Developmentin Late-Stage Development

Dipeptidyl peptidase–4 inhibitors (incretin enhancers)– Sitagliptin: Currently available– Saxagliptin: Currently available– Linagliptin: Currently available (no dose adjustment in renal

insufficiency, unlike others in class)– Vildagliptin:

Approved by EMEA Additional trials requested by FDA

– Alogliptin: NDA filed

Glucagon-like peptide–1 agonists (incretin mimetics)– Exenatide: Currently available - bid– Liraglutide: Currently available – once daily– Exenatide LAR: Currently available- once weekly– Albiglutide– Taspoglutide


Circulating GLP-1 Has Many Circulating GLP-1 Has Many Beneficial EffectsBeneficial Effects

↑ Insulin secretion to maintain glucose homeostasis ↓ Glucagon secretion ↓ Postprandial glycemia ↓ Gastric emptying ↑ Satiety due to delayed gastric emptying ↓ Food ingestion due to effects on brain ↑ Β cell number and ↑ Β cell mass (animal studies)

– ↑ Β cell proliferation and ↑ islet neogenesis– ↓ Apoptosis

Ranganath LR et al. J Clin Pathol. 2008;61:401-409.


Glucagon secretion

Glucose production

Glucose disposal

Insulin secretionInsulin biosynthesis cell proliferation cell apoptosis

Gastric emptying

CardioprotectionCardiac output

Appetite

Neuroprotection

LipogenesisOsteoblast

GLP-1

GIP

Physiological Actions of GLP-1 and GIPPhysiological Actions of GLP-1 and GIP

Sodium excretion


Comparison of Incretin Mimetics Comparison of Incretin Mimetics AvailableAvailable

Nauck M et al. In: Pharmacotherapy of Diabetes: New Developments Improving Life and Prognosis for Diabetic Patients. 2007:111-142.

Available agents: exenatide, exenatide long-acting release (LAR), liraglutide– administered by subcutaneous injection– not DDP-4 substrates

Exenatide: half-life ~2–4 hours; twice-daily injections of 5–10 mg each

Exenatide LAR: half-life >1 week; weekly injections of up to 2 mg

Liraglutide: half-life ~12–14 hours; daily injections of up to 2 mg


-1.5

-1

-0.5

0

0.5

Exenatide + Oral AgentsExenatide + Oral AgentsSummary of A1C ChangesSummary of A1C Changes

Buse JB et al. Diabetes Care. 2004;27:2628-2635 | Defronzo RA et al. Diabetes Care. 2005;28:1092-1100 | Kendall DM et al. Diabetes Care. 2005; 28:1083-1091.

““THE 3 AMIGOS TRIALTHE 3 AMIGOS TRIAL””30-Week, Randomized, Placebo-Controlled30-Week, Randomized, Placebo-Controlled


*p<0.01 vs. Placebo

A

1C

(%

)

Exenatide + Exenatide + SulfonylureaSulfonylurea

(n = 377)(n = 377)

Exenatide + Exenatide + MetforminMetformin(n = 336)(n = 336)

Exenatide + Exenatide + Sulfonylurea + Sulfonylurea +

MetforminMetformin(n = 733)(n = 733)

Placebo

Exenatide 5 µg

Exenatide 10 µg

0.12%

-0.46%*

-0.86%*

0.08%0.23%

-0.40%* -0.55%

*-0.78%

*-0.77%

*

8.6%8.6%8.6%8.6% 8.2%8.2%8.2%8.2% 8.5%8.5%8.5%8.5%


Efficacy of Exenatide BID in Clinical Efficacy of Exenatide BID in Clinical TrialsTrials

Background Therapya

Mean Disease Duration (y)

ΔA1C (%)

Exenatide BID Placebo

Monotherapy1 2 ‒0.9 ‒0.2b

MET2 5–6 ‒0.8 +0.1b

SU3 6–7 ‒0.9 +0.1b

TZD ± MET4,c 7–8 ‒0.9 +0.1b

SU + MET5 9 ‒0.8 +0.2b

a 16–30 weeks, baseline A1C: 7.8–8.6%b p<0.001 for placebo vs 10 g exenatide BIDc 79% of patients on both agents

1Moretto TJ et al. Clin Ther. 2008;30:1448-1460 | 2Defronzo RA et al. Diabetes Care. 2005;28:1092-1100 | 3Buse JB et al. Diabetes Care. 2004;27:2628-2635 | 4Zinman B et al. Ann Intern Med. 2007;146:477-485 | 5Kendall DM et al. Diabetes Care. 2005; 28:1083-1091 | 6Klonoff DC et al. Curr Med Res Opin. 2008;24:275-286.


Background Therapya


ΔA1C (%)

Liraglutide Comparators

Monotherapy1 5–61.2 mg: ‒0.81.8 mg: ‒1.1

Glim: ‒0.5b

SU2 6–71.2 mg: ‒1.11.8 mg: ‒1.1

Placebo: +0.2b

Rosi: ‒0.4b

Met3 7–81.2 mg: ‒1.0 1.8 mg: ‒1.0

Placebo: +0.1b

Glim: ‒1.0

Rosi ± Met4,c 91.2 mg: ‒1.5 1.8 mg: ‒1.5

Placebo: ‒0.5b

1Garber A, et al. Lancet. 2009;373:473-481 | 2Marre M et al. Diabet Med. 2009;26:268-278 | 3Nauck M et al. Diabetes Care. 2009;32:84-90 | 4Zinman B et al. Ann Intern Med. 2007;146:477-485 | 5Garber A et al. Diabetes Obes Metab. 2011;13:348-356.

Efficacy of Liraglutide versus Oral Efficacy of Liraglutide versus Oral Agents in Liraglutide Effect and Action Agents in Liraglutide Effect and Action in Diabetes (LEAD) Trial Seriesin Diabetes (LEAD) Trial Series

a26 weeks (except 52 weeks for monotherapy), mean baseline A1C: 8.2–8.6% bp <0.005 vs liraglutide


Efficacy of Exenatide QW versus Oral Efficacy of Exenatide QW versus Oral Agents in the DURATION Trial Series Agents in the DURATION Trial Series

Maintenance of glycemic control has been demonstrated over 3 years (ΔA1C = –1.6%)3

a 26 weeks, baseline A1C: 8.5–8.6% b p <0.05 vs exenatide QW

1Russell-Jones D et al. Diabetes Care. 2012;35:252-258 | 2Bergenstal RM et al. Lancet. 2010; 376:431-439 | 3MacConell L et al. Presented at 71st ADA Scientific Sessions (abstract 969-P), San Diego, CA, 24-28 June 2011.

DURATION = Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once-Weekly

Background Therapya


ΔA1C (%)

Exenatide QW Comparators

Monotherapy1 3 ‒1.5Met: ‒1.5Pio: ‒1.6

Sita: ‒1.2b

Met2 5–6 ‒1.5Pio: ‒1.2b

Sita: ‒0.9b


Glycemic Control with GLP-1 Receptor Glycemic Control with GLP-1 Receptor Agonists in Head-to-Head Clinical TrialsAgonists in Head-to-Head Clinical Trials

*Significant difference vs comparator GLP-1 *Significant difference vs comparator GLP-1 receptor agonistreceptor agonist

1Buse JB et al. Lancet. 2009;374:39-47 | 2Drucker DJ et al. Lancet. 2008;372:1240-1250 | 3Blevins T, et al. J Clin Endocrinol Metab. 2011;96:1301-1310 | 4Buse JB et al. Presented at 47th EASD Annual Meeting, Lisbon, Portugal, 14 September 2011.

Trial:Size (N):

Study length (weeks):

LEAD-61

46426

DURATION-12

30330

DURATION-53

25424

DURATION-64

91226

-0.8

-1.5

-0.9

-1.3-1.1

-1.9

-1.6-1.5

-2.0

-1.5

-1.0

-0.5

0.0A1

C Ch

ange

(%)

**

**

**

EXN BID

LIRA

EXN QW


-4.0

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

Exenatide + Oral AgentsExenatide + Oral AgentsSummary of Weight ChangesSummary of Weight Changes



*p<0.01 vs. placebo

W

eig

ht

(kg

)

Placebo

Exenatide 5 µg

Exenatide 10 µg

-0.6

-0.9

-1.6*

-0.3

-0.9

-1.6*

-1.6*

-2.8*

-1.6*

Buse JB et al. Diabetes Care. 2004;27:2628-2635 | Defronzo RA et al. Diabetes Care. 2005;28:1092-1100 | Kendall DM et al. Diabetes Care. 2005; 28:1083-1091.

Exenatide + Exenatide + SulfonylureaSulfonylurea

(n = 377)(n = 377)

Exenatide + Exenatide + MetforminMetformin(n = 336)(n = 336)

Exenatide + Exenatide + Sulfonylurea + Sulfonylurea +

MetforminMetformin(n = 733)(n = 733)


Changes in Body Weight with Exenatide Changes in Body Weight with Exenatide versus Insulinversus Insulin

Reprinted with permission from Heine R et al. Ann Intern Med. 2005;143:559–569. Copyright © 2005 American College of Physicians. All rights reserved.

*P<0.0001 compared with insulin glargine measure at the same time point.

-3

-2

-1

0

1

2

Ch

an

ge in

Bod

y W

eig

ht

(kg

)

Weeks

40 12 261882

Exenatide group (n = 275)

**

* **

*

Insulin glargine group (n = 260)


Distribution of Weight Loss and A1C Distribution of Weight Loss and A1C Change with Exenatide BID and Exenatide Change with Exenatide BID and Exenatide QWQW

Reprinted with permission from Drucker DJ et al. Lancet. 2008;372: 1240-1250. Copyright © 2008 Elsevier. All rights reserved.

Once a week (73%)Twice a day (74 %)

Once a week (1%)Twice a day (5%)

Once a week (3%)Twice a day (5%)

Once a week (23%)Twice a day (16%)10

0

-10

-20

-30

-40-6 -5 -4 -3 -2 -1 0 1 2 3

A1C Change (%)

Wei

gh

t C

han

ge

(kg

)


Comparison of Incretin ModulatorsComparison of Incretin Modulators

GLP-1 Analogues DPP-4 Inhibitors

Administration route Injection Oral

GLP-1 Sustained Meal-related

Effect on A1C

Effects on body weight

Side effectsNausea,

Rare: pancreatitis

(Well tolerated) Nasopharyngitis, skin rashes, Stevens-Johnson syndrome

-cell function

GLP-1=glucagon-like peptide–1; DDP-4=dipeptidyl peptidase–4


Cardiovascular Effects of GLP-1 Cardiovascular Effects of GLP-1 AnalogsAnalogs

Beneficial BP effects – Rapid– Probably not due to weight loss– May be direct vascular effects or natriuretic effects– Weight loss may contribute to sustained reductions

Beneficial effects on lipids, other CVD risk factors– Largely mediated through weight loss

May have direct cardioprotective effects


Combination of Basal Insulin with a Combination of Basal Insulin with a GLP-1 Agonist Has a Scientific LogicGLP-1 Agonist Has a Scientific Logic

Basal insulin analogs• Simple to initiate• Control nocturnal and FPG• Lower hypoglycaemia risk vs NPH• Modest weight increase (1–3 kg)• Achieve A1C targets in ~50–60%

GLP-1 agonists• Simple to initiate• Pronounced PPG control• No increase in hypoglycaemia• Weight lowering/neutral effects• Achieve A1C targets in ~40–60%

Complementary actions

Additive effects


Exenatide BID Combined with Exenatide BID Combined with Basal InsulinBasal Insulin

More patients discontinued EXN BID (9%) vs PBO (1%) due to adverse events (p <0.01)1

Significant A1C reduction regardless of intensification order2

– EXN BID + insulin glargine

– Insulin glargine + EXN BID

1Buse JB et al. Ann Intern Med. 2011;154:103-112 | 2Levin PA, et al. Endocr Pract. 2012;18:17-25.

EXN BID + GLAR vs PBO + GLAR1 30-Week Trial (N = 259)

p <0.001


Kruger DF et al. Diabetes Educ. 2010;36(suppl 3):44S-72S | Amylin Pharmaceuticals, Byetta prescribing information, December 2011 | Amylin Pharmaceuticals, Bydureon prescribing information, January 2012 | Novo Nordisk, Victoza prescribing information, April 2012.

Managing Nausea Associated with GLP-1 Managing Nausea Associated with GLP-1 Receptor AgonistsReceptor Agonists Discuss expectations

– Nausea is likely to be mild and resolve in a few weeks– Nausea may actually be “fullness”

Suggest decreased portion sizes Suggest reduced fat content of meals

– Keep a log of foods that cause nausea Be aware of severe persistent abdominal pain, which could indicate

pancreatitis Titrate more slowly – maintain at lower dose for a longer period Be aware of severe GI disease

– GLP-1 receptor agonists slow gastric emptying and are associated with GI adverse events

– GLP-1 receptor agonists have not been studied in patients with severe GI disease

– Avoid exenatide in patients with history of gastroparesis


0.0 0.5 1.0 1.5 2.0

Relative Risk of Acute Pancreatitis (±95% CI)

• The absolute risk of acute pancreatitis was comparable among initiators of exenatide and sitagliptin

Dore DD et al. Curr Med Res Opin. 2009;25(4):1019–1027.

Absolute and Relative Risk of Acute Pancreatitis Absolute and Relative Risk of Acute Pancreatitis with Antidiabetic Agents in Human Subjectswith Antidiabetic Agents in Human Subjects

Exenatide-Met/GlySitagliptin-Met/Gly

Drug Pair 1: Exenatide 0.13% (N = 27,996); Met/Gly 0.13% (N = 27,983)Drug Pair 2: Sitagliptin 0.12% (N = 16,267); Met/Gly 0.12% (N = 16,281)


Incretin-Based Therapies: Incretin-Based Therapies: Reports of Pancreatitis Reports of Pancreatitis

Patients with diabetes should be counseled about the symptoms of pancreatitis

Symptoms include persistent abdominal pain that can radiate to the back and may or may not be accompanied by nausea and vomiting

Exenatide and liraglutide should be stopped if signs of pancreatitis develop and should be used with caution in patients who have a history of the disease


Liraglutide and Exenatide ER: Liraglutide and Exenatide ER: Boxed WarningBoxed Warning

Warning: risk of thyroid C-cell tumors

[Liraglutide/Exenatide extended-release] causes thyroid C-cell tumors at clinically relevant exposures in rodents

Unknown whether [Victoza/Bydureon] causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be determined by clinical or nonclinical studies

Contraindicated in patients with:– Personal or family history of MTC – Multiple endocrine neoplasia syndrome type 2 (MEN 2)

Amylin Pharmaceuticals, Bydureon prescribing information, January 2012 | Novo Nordisk, Victoza prescribing information, April 2012.


DPP-4 Inhibitors vs. GLP-1 AgonistsDPP-4 Inhibitors vs. GLP-1 Agonists

DPP-4 inhibitorsDPP-4 inhibitors– GLP-1 and GIP enhancedGLP-1 and GIP enhanced– Physiological fluctuationsPhysiological fluctuations

in hormone levels in hormone levels – Limited by endogenous Limited by endogenous

secretionsecretion– Comparable to TZD, SUComparable to TZD, SU– Superior tolerabilitySuperior tolerability– Weight neutralWeight neutral– Oral, once dailyOral, once daily

GLP-1 agonistsGLP-1 agonists– Pure GLP-1 effectPure GLP-1 effect– Sustained effect that maySustained effect that may

be prolonged be prolonged – Not limited by endogenous Not limited by endogenous

secretionsecretion– Superior to SU, TZDSuperior to SU, TZD– Nausea, vomiting Nausea, vomiting – Weight lossWeight loss– InjectionInjection


Comparison of Dipeptidyl Peptidase–4 Comparison of Dipeptidyl Peptidase–4 (DPP-4) Inhibitors(DPP-4) Inhibitors

Sitagliptin Linagliptin Saxagliptin Vildagliptin

Usual phase 3 dose 100 mg QD 5 mg QD 5 mg QD 50 mg BD

Half-life (t1/2), h 12.4 12.5–21.1 2.2–3.8 1.3–2.4

DPP-4 inhibition at 24 h

~80% ~80% (25 mg) ~55% (5 mg) 50% (100 mg)

Elimination Kidney(mostly unchanged)

Bile but not kidney(mostly unchanged)

Liver and kidneyActive metabolite

Kidney>>LiverInactive metabolite

Renal dose adjustments required

Yes No Yes None for mild impairment; not

recommended for moderate or severe

impairment

Selectivity for DPP-4 >2600-fold vs DPP-8 >10,000-fold vs DPP-9

>10,000-fold vs DPP-8/9

>400-fold vs DPP-8>100-fold vs DPP-9

>90-fold vs DPP-8

Potential for drug–drug interaction

Low Low Strong CYP3A4/5 inhibitors

Low

Food effect No No No No


Properties of Dipeptidyl Peptidase–4 Properties of Dipeptidyl Peptidase–4 (DPP-4) Inhibitors(DPP-4) Inhibitors

Nauck M et al. In: Pharmacotherapy of Diabetes: New Developments Improving Life and Prognosis for Diabetic Patients. 2007:111-142.

Oral administrationOral administration

GLP-1/GLP-1 receptor agonist concentration elevated 3–6 hours GLP-1/GLP-1 receptor agonist concentration elevated 3–6 hours after meals when secretion from endogenous sources is after meals when secretion from endogenous sources is stimulatedstimulated

GLP-1 concentration close to physiological concentration (~ x 2–3)GLP-1 concentration close to physiological concentration (~ x 2–3)

Action through GLP-1 receptors and possibly GIP receptors and/or Action through GLP-1 receptors and possibly GIP receptors and/or other receptorsother receptors

GLP-1 action probably through nerves more than circulationGLP-1 action probably through nerves more than circulation

A1C reduction −0.5% to −1.1%A1C reduction −0.5% to −1.1%

Weight change ±0 kgWeight change ±0 kg

-Cell mass effects probable in animals, no human data -Cell mass effects probable in animals, no human data


Mean

Ch

an

ge f

rom

B

aselin

e in

A1C

(%

)

–0.9

–1.1

-2.0

-1.8

-1.6

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

–0.8

–1.0

vs Placebo

vs RSG

vs Met

Monotherapy

*Initial combination therapyAll statistically significant

Insulin >30 U/d

Pio 45 mg qd

–1.9

Add-on Combination TherapyMet ≥1500 mg/d

Pio* 30 mg qd

–0.5

–0.9–0.8

Vildagliptin: A1C ChangesVildagliptin: A1C Changes

Reprinted with permission from Rosenstock J et al. Curr Opin Endocrinol Diabetes Obes. 2007;14:98-107. Copyright © 2007 Wolters Kluwer Health. All rights reserved.

Study duration (wks) 24 24 24 52 24 24 24 24

N (ITT population) 380 340 697 780 416 398 592 256

Baseline A1C (%) 8.4 8.3 8.7 8.7 8.4 8.7 8.8 8.5


vs Placebo

Mean

ch

an

ge f

rom

b

aselin

e in

Hb

A1c (

%)

-0.6-0.5

vs Glipizide

-0.7

-0.5

-0.85

Pio 30–45

mg/d

Met*2000 mg/d

-1.9

Sitagliptin: A1C ChangesSitagliptin: A1C Changes

Study duration (wks) 24 18 24 52 24 24

N (ITT population) 711 495 677 1135 1056 337

Baseline A1C (%) 8.0 8.1 8.0 7.7 8.8 8.1

*Initial combination therapyAll statistically significant

vs Placebo

Monotherapy Add-on Combination Therapy

-2.0

-1.8

-1.6

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

Met ≥1500 mg/d

Reprinted with permission from Rosenstock J et al. Curr Opin Endocrinol Diabetes Obes. 2007;14:98-107. Copyright © 2007 Wolters Kluwer Health. All rights reserved.


Efficacy of Add-on SitagliptinEfficacy of Add-on Sitagliptin

LSM = least-squares mean change

1Charbonnel B et al. Diabetes Care 2006;29:2638-2643 |2Rosenstock J et al. Clin Ther 2006;28:1556-1568.

–0.65% (P<0.001)

–0.70% (P<0.001)

1 2


Similar Glycemic Control with Sitagliptin Similar Glycemic Control with Sitagliptin vs Glipizide Added to Metformin vs Glipizide Added to Metformin

Sitagliptin 100 mg qd (n=382)

Glipizide (n=411)

Mean

ch

an

ge in

A1

C

Mean change from baseline (for both groups)*: –0.67%

6.0

6.2

6.4

6.6

6.8

7.0

7.2

7.4

7.6

7.8

8.0

8.2

8.4

0 12 24 38 52Time (weeks)

*Per protocol analysis; –0.51% and –0.56% for sitagliptin and glipizide, respectively, in last observation carried forward (LOCF) analysis

Reprinted with permission from Nauck MA et al. Diabetes Obes Metab. 2007; 9:194-205. Copyright © 2007 John Wiley and Sons. All rights reserved.


-0.8

-0.6

-0.4

-0.2

0

0.2

0.4 0.19

–0.54*–0.45*–0.43*A

dju

sted m

ean ±

SE

change in A

1C

(%)

Reprinted with permission from Rosenstock J et al. Curr Med Res Opin. 2009; 25:2401-2411. Copyright © 2009 Informa Healthcare. All rights reserved.

Saxagliptin Monotherapy in Treatment-NaSaxagliptin Monotherapy in Treatment-Naïve ïve Patients with Type 2 DiabetesPatients with Type 2 Diabetes

*P<0.0001 vs PBO

-0.8

-0.6

-0.4

-0.2

0.0

0.2

0.4

BL 4 6 8 12 16 20 24

Weeks

Mean ±

SE c

hange in

A1

C f

rom

base

line (

%)

PBO

SAXA 5 mg

SAXA 2.5 mg

SAXA 10 mg

2.5 5 10

7.9 8.0 7.9 7.9

Dose

Baseline mean A1C

(%)

PBO

SAXA (mg)

2.5 5 10 PBO100 103 95 92

7.9 8.0 7.9 7.9

Dose

n =

SAXA (mg)

Baseline mean A1C

(%)


-0.8

-0.6

-0.4

-0.2

0

0.2

BL 4 8 12 16 20 24BL

Saxagliptin Add-on to Metformin: Reduction Saxagliptin Add-on to Metformin: Reduction in A1C in Patients with Type 2 Diabetes in A1C in Patients with Type 2 Diabetes Inadequately Controlled on Metformin AloneInadequately Controlled on Metformin Alone

Reprinted with permission from DeFronzo RA et al. Diabetes Care. 2009;32:1649-1655. Copyright © 2009 American Diabetes Association. All rights reserved.

A1

C,

Mean

± S

E C

han

ge

from

Baselin

e (

%)

SAXA 5 mg + MET

SAXA 2.5 mg + MET

SAXA 10 mg + MET

PBO + MET

6


Efficacy of Saxagliptin Monotherapy Efficacy of Saxagliptin Monotherapy Therapy over 24 Weeks Compared with Therapy over 24 Weeks Compared with PlaceboPlacebo

SAXA = saxagliptinFPG = fasting plasma glucosePPG-AUC = postprandial glucose area under the curve

* Placebo-subtracted difference† Statistically significant decrease from baseline

SAXA Dose(Main treatment cohort)

A1C Change (%)*

FPG Change (mg/dL)*

PPG-AUC Change(mg + min/dL)*

2.5 mg once daily −0.62† −21† −6221

5.0 mg once daily −0.64† −15† −6249†

10.0 mg once daily −0.73† −23† −7437†

Rosenstock J et al. Curr Med Res Opin. 2009;25:2401-2411.


Prandial Glucagon after up to 2 Years Add-on Prandial Glucagon after up to 2 Years Add-on Treatment in Patients with Type 2 Diabetes Treatment in Patients with Type 2 Diabetes Inadequately Controlled with Metformin Inadequately Controlled with Metformin

Vildagliptin

Glimepiride

Glu

cag

on

(p

mol.

hr/

L)

0

1

2

3

4

5

-1

-2

-3

-4

-5

p<0.001 for difference between treatment groups

Reprinted with permission from Ahrén B et al. Diabetes Care. 2010;33:730-732. Copyright © 2010 American Diabetes Association. All rights reserved.


Vildagliptin

Glimepiride

Insu

lin

Secre

tory

Rate

R

ela

tive t

o G

lucose

(pm

ol/

min

/m2

/mm

ol/

L)

3.0

4.0

5.0

0.5

0

1.5

2.5

3.5

4.5

2.0

1.0

p=0.022 for difference between treatment

groups

Insulin Secretory Rate Relative to Glucose after up Insulin Secretory Rate Relative to Glucose after up to 2 Years Add-on Treatment in Patients with Type 2 to 2 Years Add-on Treatment in Patients with Type 2 Diabetes Inadequately Controlled with Metformin Diabetes Inadequately Controlled with Metformin

Ahrén B et al. Diabetes Care. 2010;33:730-732.


Adverse Events with Dipeptidyl Adverse Events with Dipeptidyl Peptidase–4 (DPP-4) InhibitorsPeptidase–4 (DPP-4) Inhibitors

Amori RE et al. JAMA. 2007;298:194-206.

Adverse EventsNo. of Studies

Risk Ratio DPP-4 vs. Control

Mean % Experiencing Outcome

DPP-4 Control

Hypoglycemia 20 0.97 1.6% 1.4%

Nausea 10 0.89 2.7% 3.1%

Vomiting 6 0.69 1.3% 1.5%

Diarrhea 7 0.80 3.8% 4.0%

Abdominal pain 5 0.73 2.4% 3.2%

Cough 5 1.07 2.9% 2.4%

Influenza 6 0.87 4.1% 4.7%

Nasopharyngitis 12 1.17 6.4% 6.1%

Upper respiratory tract infection 9 0.99 6.3% 6.4%

Sinusitis 3 0.61 2.0% 3.4%

Urinary tract infection 5 1.52 3.2% 2.4%

Headache 13 1.38 5.1% 3.9%

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