PrevalenceofDiabetesandPrediabetes Update on Diabetes ...€¦ · Diabetes Care 2012;35:1364–1379...

Update on Diabetes Medications

TNP Primary Care

and Pharmacology Update

Tom Blevins MD Texas Diabetes and Endocrinology

Austin, Texas

Prediabetes

35% of U.S. popula6on

Diabetes

8.3% of U.S. popula6on

Undiagnosed

Diagnosed

Prevalence of Diabetes and Prediabetes in the United States

Centers for Disease Control and Prevention. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed February 11 2011.

Persons (millions)

Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials

Study Microvasc CVD Mortality

UKPDS ê! ê! çè! ê! çè! ê!DCCT / EDIC* ê! ê! çè! ê! çè! ç

è!ACCORD ê! çè! é!ADVANCE ê! çè! çè!

VADT ê! çè! çè!Long Term Follow-‐up

Ini6al Trial

* in T1DM

Kendall DM, Bergenstal RM. © International Diabetes Center 2009 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854. Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977. Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545. Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum: Moritz T. N Engl J Med 2009;361:1024)

Type 2 Diabetes: UKPDS

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

3. ANTI-‐HYPERGLYCEMIC THERAPY

•  Glycemic targets

-  HbA1c < 7.0% (mean PG ∼150-‐160 mg/dl [8.3-‐8.9 mmol/l])

-  Pre-‐prandial PG <130 mg/dl (7.2 mmol/l)

-  Post-‐prandial PG <180 mg/dl (10.0 mmol/l)

-  Individualiza6on is key: Ø  Tighter targets (6.0 -‐ 6.5%) -‐ younger, healthier Ø  Looser targets (7.5 -‐ 8.0%+) -‐ older, comorbidiUes, hypoglycemia prone, etc.

-  Avoidance of hypoglycemia

PG = plasma glucose Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

Initial drug monotherapy

Efficacy (! HbA1c) Hypoglycemia Weight Side effects Costs

Healthy eating, weight control, increased physical activity

Metformin high low risk neutral/loss GI / lactic acidosis low

If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (order not meant to denote any specific preference):

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Efficacy (! HbA1c) Hypoglycemia Weight Major side effect(s) Costs

high low risk gain edema, HF, fx’s‡ high

Thiazolidine- dione

intermediate low risk neutral rare‡

high

DPP-4 Inhibitor

highest high risk gain hypoglycemia‡

variable

Insulin (usually basal)

Two drug combinations*

Sulfonylurea† +

Thiazolidine-dione +

DPP-4 Inhibitor +

GLP-1 receptor agonist +

Insulin (usually basal) +

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

TZD

DPP-4-i

GLP-1-RA

Insulin§

SU†

DPP-4-i

GLP-1-RA

Insulin§

SU† SU†

TZD TZD

TZD

DPP-4-i

Insulin§ Insulin§

If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months, proceed to a more complex insulin strategy, usually in combination with 1-2 non-insulin agents:

Insulin# (multiple daily doses)

Three drug combinations

More complex insulin strategies

or

or

or

or

or

or

or

or

or

or

or

or GLP-1-RA

high low risk loss GI‡ high

GLP-1 receptor agonist

Sulfonylurea†

high moderate risk gain hypoglycemia‡ low


T2DM An6-‐hyperglycemic Therapy: General Recommenda6ons Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596





Metformin +

Metformin +

Metformin +

Metformin +

Metformin +



Thiazolidine- dione


high

DPP-4 Inhibitor


variable



Sulfonylurea† +


DPP-4 Inhibitor +



Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

TZD

DPP-4-i

GLP-1-RA

Insulin§

SU†

DPP-4-i

GLP-1-RA

Insulin§

SU† SU†

TZD TZD

TZD

DPP-4-i

Insulin§ Insulin§




or

or

or

or

or

or

or

or

or

or

or

or GLP-1-RA



Sulfonylurea†



Recommenda6ons: When Goal is to Avoid Weight Gain Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596





Metformin +

Metformin +

Metformin +

Metformin +

Metformin +



Thiazolidine- dione


high

DPP-4 Inhibitor


variable



Sulfonylurea† +


DPP-4 Inhibitor +



Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

TZD

DPP-4-i

GLP-1-RA

Insulin§

SU†

DPP-4-i

GLP-1-RA

Insulin§

SU† SU†

TZD TZD

TZD

DPP-4-i

Insulin§ Insulin§




or

or

or

or

or

or

or

or

or

or

or

or GLP-1-RA



Sulfonylurea†




Recommenda6ons: When Goal is to Avoid Hypoglycemia Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596





Metformin +

Metformin +

Metformin +

Metformin +

Metformin +



Thiazolidine- dione


high

DPP-4 Inhibitor


variable



Sulfonylurea† +


DPP-4 Inhibitor +



Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

TZD

DPP-4-i

GLP-1-RA

Insulin§

SU†

DPP-4-i

GLP-1-RA

Insulin§

SU† SU†

TZD TZD

TZD

DPP-4-i

Insulin§ Insulin§

If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months, proceed to a more complex insulin strategy, usually in combination with 1-2 non-insulin agents:




or

or

or

or

or

or

or

or

or

or

or

or GLP-1-RA



Sulfonylurea†




Recommenda6ons: When Goal is to Minimize Costs Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

4. OTHER CONSIDERATIONS •  Age •  Weight •  Sex / racial / ethnic / gene6c differences •  Comorbidi6es

-‐  Coronary artery disease -‐  Heart Failure -‐  Chronic kidney disease -‐  Liver dysfunc6on -‐  Hypoglycemia

Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

n  Prevalence of diabetes among U.S. adults aged 65 or more years varies from 22 to 33%, depending on the diagnostic criteria used.

n  Postprandial hyperglycemia is a prominent characteristic of type 2 diabetes in older adults.

Journal of the American Geriatric Society, December 2012–VOL. 60, NO. 12

a. Coexisting chronic illnesses are conditions serious enough to require medications or lifestyle management and may include arthritis, cancer, congestive heart failure, depression, emphysema, falls, hypertension, incontinence, stage III or worse chronic kidney disease, MI, and stroke. By multiple we mean at least three, but many patients may have five or more.

b.  The presence of a single end-stage chronic illness such as stage III–IV congestive heart failure or oxygen-dependent lung disease, chronic kidney disease requiring dialysis, or uncontrolled metastatic cancer may cause significant symptoms or impairment of functional status and significantly reduce life expectancy.

c.   A1C of 8.5% equals estimated average glucose of ~200 mg/dL. Looser glycemic targets than this may expose patients to glycosuria, dehydration, hyperglycemic hyperosmolar syndrome, and poor wound healing.

Case Presenta6on -‐ Mary

•  Mary, a 58-‐year-‐old woman with a history of diabetes, hypertension and hyperlipidemia, comes to see you for worsening blood glucose control

•  She was diagnosed with diabetes mellitus 3 years ago when she presented with blood glucose of 338 mg/dL

•  Her treatment regimen has been me\ormin 1000 mg twice daily, along with an unsuccessful diet and exercise program

•  Over the last 6 months, her blood glucose has been elevated; her current hemoglobin A1C is 8.6%

•  The rest of her labs are unremarkable; her physical exam is unremarkable except for acanthosis nigricans and a BMI of 38 kg/m²

mg=milligram; dL=deciliter; kg=kilogram; m²= meters squared; BMI=body mass index.

Which of the following treatment op6ons would most likely

get Mary’s A1C to goal and assist with some weight loss?

1.  GLP-‐1 agonist 2.  TZD 3.  Sulfonylurea 4.  Alpha-‐glucosidase inhibitor 5.  SGLT-‐2 inhibitor

A1C=glycated hemoglobin; GLP-‐1=glucagon-‐like pepUde 1; TZD=thiazolidinedione; SGLT-‐2=sodium glucose cotransporter 2

Main Pathophysiological Defects in T2DM “The Ominous Octet”

Islet β-cell

Impaired Insulin Secretion

Neurotransmitter Dysfunction

Decreased Glucose Uptake

Islet α-cell

Increased Glucagon Secretion

Increased Lipolysis

Increased Glucose Reabsorption

Increased Hepatic Glucose Production

Decreased Incretin Effect

DeFronzo RA, Diabetes. 2009;58:773-95.

Mechanism ê HepaUc glucose producUon êê FPG more than PPG

Efficacy ê A1C 1%-‐2%

Advantages No weight gain or hypoglycemia

Disadvantages GI side effects LacUc acidosis (rare)

Contraindica6ons Renal disease; CHF

CombinaUons available with SU, TZD, repaglinide, and DPP-‐4 inhibitors

Biguanides Metformin

Metformin [package insert]. Princeton NJ; Bristol Myers Squibb; 2009.

A1C = glycated hemoglobin; CHF = congesUve heart failure; DPP-‐4 = dipepUdyl pepUdase-‐4; FPG = fasUng plasma glucose; GI = gastrointesUnal; PPG = post-‐prandial glucose; SU = sulfonylurea; TZD = thiazolidinedione

Sulfonylureas Glipizide, Glimepiride, Glyburide

Mechanism é Insulin secreUon ê FPG ê PPG

Efficacy Moderate

Advantages Strong short term efficacy

Disadvantages Weight gain, hypoglycemia, tend to loose efficacy amer several years

Contraindica6ons Avoid in severe hepaUc and renal impairment

CombinaUons available with me\ormin, TZD

Glyburide [package insert]. New York, NY; Pfizer; 2010. Glipizide [package insert]. New York, NY; Pfizer; 2010. Glimepiride [package insert]. Scoppito, Italy; Aventis Pharma S.p.A; 2001. Kahn SE, et al. NEJM. 2006;355:23.

FPG = fasUng plasma glucose; PPG = post-‐prandial glucose; TZD = thiazolidinedione

Thiazolidinediones Pioglitazone, Rosiglitazone

Mechanism ↑ Insulin sensiUvity, especially at muscle, lowers both FPG and PPG, but effect may be delayed

Efficacy Moderate (↓ A1C 1.0%-‐1.5%)

Advantages No hypoglycemia, no reliance on renal excreUon

Disadvantages

Fluid retenUon, edema, heart failure, weight gain, slow onset of acUon, bone fractures, macular edema, osteoporosis, anemia and bladder cancer

Contraindica6ons Class III or IV CHF or hepaUc impairment w/ALT >2.5 Umes upper normal limits

CombinaUons available with me\ormin and sulfonylurea

Pioglitazone [package insert]. Deerfield, IL: Takeda Pharmaceuticals America. 2011; Rosiglitazone Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline. 2013

A1C = glycated hemoglobin; ALT = alanine aminotransferase; CHF = congesUve heart failure; FPG = fasUng plasma glucose; PPG = post-‐prandial glucose

Alpha-‐Glucosidase Inhibitors Acarbose, Miglitol

Mechanism ↓ Rate of gut polysaccharide breakdown, thereby slowing absorpUon

Efficacy Modest (↓ A1C 0.5%-‐1.0%), PPG lowering

Advantages Weight-‐neutral, non-‐systemic drug, targets post-‐prandial glucose

Disadvantages BloaUng, flatulence, diarrhea – ↓ w/slow UtraUon, frequent dosing

Contraindica6ons Severe renal impairment, diabeUc ketoacidosis, malabsorpUon, obstrucUon, inflammatory bowel, or condiUons aggravated by gas producUon

CombinaUons available with sulfonylureas

Acarbose [package insert]. Wayne, NJ; Bayer HealthCare Pharmaceuticals Inc.; 2009. Miglitol [package insert]. Wayne, NJ; Bayer HealthCare Pharmaceuticals Inc.; 2010.

A1C = glycated hemoglobin; PPG = post-‐prandial glucose

Synthe6c Human Amylin Analog Pramlin6de

Pramlintide [package insert]. San Diego, CA; Amylin Pharmaceuticals, Inc; 2008.

Mechanism Amylin mimeUc: êPPG, suppresses glucagon secreUon, slows gastric emptying, promotes saUety

Efficacy Modest ( ê A1C 0.5%)

Advantages No dosage adjustment required in renal impairment

Disadvantages

Nausea, headaches, anorexia, vomiUng, abdominal pain, faUgue, dizziness, coughing, pharyngiUs, risk of severe hypoglycemia with insulin

Contraindica6ons Confirmed diagnosis of gastroparesis, hypoglycemia unawareness

GLP-‐1 Modulates Numerous Func6ons in Humans

Stomach: Helps regulate

gastric emptying

Promotes satiety and reduces appetite

Liver: ↓ Glucagon

reduces hepatic glucose output

Beta-cells: Enhances glucose-

dependent insulin secretion

Alpha-cells: ↓ Glucose-dependent

postprandial glucagon secretion

1. Data from Flint A, et al. J Clin Invest. 1998;101:515-520; 2. Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422 3. Data from Nauck MA, et al. Diabetologia. 1996;39:1546-1553; 4. Data from Drucker DJ. Diabetes. 1998;47:159-169

GLP-‐1=glucagon-‐like pepUde 1.

GLP-1: Secreted upon the ingestion

of food

Healthy (n = 11) Type 2 diabetes (n = 12)

Mean ± SE

Müller WA, et al. N Engl J Med. 1970;283:109-115

140

360 300 240

Glucose (mg/dL)

0

120 60

Insulin (mcU/mL)

100

120 140

Glucagon (pg/mL)

80

-60 120 180 240 Time (min) 60 0

Meal

Abnormal Insulin and Glucagon Responses Contribute to Hyperglycemia in Type 2 Diabetes

mg=milligram; dL=deciliter; mcU=micro units; mL=mililiters; pg=pico grams; min=minutes.

Incre6n-‐based Therapy

1.  Handelsman Y; AACE. Endocr Pract. 2011 Mar-Apr;17 Suppl 2:1-53. 2.  Garber AJ, et al. Endocr Pract. 2013;19:327-336.

GLP-‐1 analog DPP-‐4 inhibitor Lowers FPG and PPG Predominately lowers PPG Slight loss Weight-‐neutral A1C reducUons 0.9%-‐1.8% A1C reducUons 0.5%-‐0.9% Works at any Ume point in type 2 diabetes

Works at any Ume point in type 2 diabetes

FPG=fasUng plasma glucose; PPG=postprandial glucose; DPP-‐4=dipepUdyl pepUdase-‐4; GLP-‐1=glucagon-‐like pepUde-‐1; A1C=glycated hemoglobin.

DPP 4 Inhibitors

Characteris6cs of DPP-‐4 Inhibitors Aloglip6n, Linaglip6n, Saxaglip6n, Sitaglip6n, Vildaglip6n

Mechanism Inhibit enzymaUc degradaUon of GLP-‐1 and GIP; glucose-‐dependent

Efficacy Decrease A1C levels 0.6%–0.9%

Dosing Once daily

Side effects Headaches, nasopharyngiUs

Main risk Viral infecUon; long-‐term safety unknown

Rosenstock J, et al. Curr Opin Endocrinol Diabetes Obes. 2007;14:98-107. Nathan DM, et al. Diabetes Care. 2008;31:173-175.

A1C = glycated hemoglobin; GIP = gastric inhibitory polypepUde; GLP-‐1 = glucagon-‐like pepUde-‐1

*P<0.001 vs acUve comparator monotherapy. †P<0.001 vs acUve comparator dual therapy. 1. Nauck MA, et al. Diabetes Obes Metab. 2007;9:194-205. 2. Goldstein BJ, et al. Diabetes Care. 2007;30:1979-1987. 3. Charbonnel B, et al. Diabetes Care. 2006;29:2638-2643. 4. Vilsbøll T, et al. Diabetes Obes Metab. 2010;12:167-177. 5. Derosa G, et al. Metab Clin Exp. 2010;59:887-895. 6. agliptinagliptin prescribing information. Whitehouse Station, NJ: Merck & Co. Inc. 2010.

Δ A1C

(%)

Glucose Control with Sitaglip6n Selected Mono and Combina6on Therapy Studies

Monotherapy vs Glipizide 52 Weeks1

Ini6al Combo w/ Mehormin 24 Weeks2

Add-‐on to Mehormin 24 Weeks3

Add-‐on to Insulin

24 Weeks4

Add-‐on to Pioglitazone vs

Met+Pio 12 Months5

Add-‐on to Rosiglitazone + Mehormin 54 Weeks6

N 1091 701 641 151 641

Treatment (mg/day)

Sit Glip Sit Met Sit+ Met

Met Sit+ Met

Ins Sit+ Ins

Met + Pio

Sit + Pio

Rosi + Met

Sit + Rosi + Met

Baseline A1C (%)

7.5 7.5 8.9 8.7 8.8 8.0 8.0 8.6 8.7 8.4 8.5 8.6 8.7

*

* * †

Sit=sitaglipUn; Glip=glipizide; Sit=sitaglipUn; Met=me\ormin; Ins=insulin; Pio=pioglitazone; Rosi=rosiglitazone; A1C=glycated hemoglobin; mg=miligram.

*P<0.001 vs glipizide; †P<0.05 vs sitagliptin 1. Aschner P, et al. Diabetes Care. 2006;29:2632-2637. 2. Nauck MA, et al. Diabetes Obes Metab. 2007;9:194-205. 3. Rosenstock J, et al. Clin Ther. 2006;28:1556-1568. 4. Hermansen K, et al. Diabetes Obes Metab. 2007;9:733-745. 5. Vilsbøll T, et al. Diabetes Obes Metab. 2010;12:167-177. 6. Derosa G, et al. Metab Clin Exp. 2010;59:887-895.

Δ W

eigh

t (kg

) Weight Changes with Sitaglip6n

Selected Mono and Combina6on Therapy Studies

† *

Monotherapy 24 Weeks1


Add-‐on to Pioglitazone 24 Weeks3

Add-‐on to Glimepiride 24 Weeks4


24 Weeks5

Add-‐on to Pio vs Met + Pio 12 Months6

N 741 793 353 441 641 151

Treatment PBO Sit Glip Sit Pio Sit + Pio

Glim Sit + Glim

Ins Sit + Ins

Met + Pio

Sit + Pio

Sit=sitaglipUn; Glip=glipizide; Sit=sitaglipUn; Met=me\ormin; Ins=insulin; Pio=pioglitazone; Glim=glimepiride; A1C=glycated hemoglobin; mg=miligram; PBO=placebo.

Hypoglycemia with Sitaglip6n Selected Studies

Pat

ient

s R

epor

ting

Hyp

ogly

cem

ia (%

)

1. Nauck MA, et al. Diabetes Obes Metab. 2007;9:194-205. 2. Goldstein BJ, et al. Diabetes Care. 2007;30:1979-1987. 3. Charbonnel B, et al. Diabetes Care. 2006;29:2638-2643. 4. Rosenstock J, et al. Clin Ther. 2006;28:1556-1568. 5 . Hermansen K, et al. Diabetes Obes Metab. 2007;9:733-745. 6. Vilsbøll T, et al. Diabetes Obes Metab. 2010;12:167-177.

Sitaglip6n vs Glipizide 52 weeks1

Ini6al Combo w/Mehormin 24 Weeks2


Add-‐on to Pioglitazone 24 Weeks4

Add-‐on to Glimepiride 24 Weeks5


24 Weeks6

N 793 1091 701 353 441 641

Treatment Sit Glip Met Sit + Met

Met Sit + Met

Pio Sit + Pio

Glim Sit + Glim

Sit + Glim + Met

Ins Sit + Ins

Sit=sitaglipUn; Glip=glipizide; Sit=sitaglipUn; Met=me\ormin; Ins=insulin; Pio=pioglitazone; Glim=glimepiride; A1C=glycated hemoglobin; mg=miligram; deciliter; PBO=placebo.

Incidence of Selected Adverse Events with Sitaglip6n: Pooled Data

Adverse Event Incidence per 100 pa6ent-‐years

Difference (95% CI) Sitaglip6n 100 mg Non-‐exposed

ConsUpaUon 2.6 1.9 0.8 (0.1, 1.4)

Diarrhea 6.9 9.6 -‐2.3 (-‐3.6, -‐1.0)

Headache 5.8 5.6 0.4 (-‐0.7, 1.4)

NasopharyngiUs 7.7 7.0 0.9 (-‐0.3, 2.1)

PancreaUUs 0.08 0.10 -‐0.02 (-‐0.20, 0.14)

Rash 1.3 0.9 0.4 (-‐0.1, 0.8)

Upper respiratory infecUon 8.6 9.0 -‐0.3 (-‐1.6, 1.0)

Williams-Herman D, et al. BMC Endocr Disord. 2010;10(7); Engel SS, et al. Int J Clin Pract. 2010;64:984-990.

mg=milligrams; CI=confidence interval

Glucose Control with Saxaglip6n Mono and Combina6on Therapy

*

Δ A

1C (%

)

*

*

* *


Ini6al Combo w/Mehormin 24 Weeks2



Add-‐on to Glyburide vs Up6tra6on 24 Weeks5

Add-‐on to TZD

24 Weeks6

N 401 1306 743 801 768 565

Treatment PBO Sax Met Sax + Met

Met Sax + Met

Sit + Met

Sax + Met

Gly Sax + Gly

TZD Sax + TZD

Baseline A1C (%) 8.0 7.9 9.4 9.4 8.1 8.1 7.7 7.7 8.4 8.5 8.2 8.4

* P<0.0001 vs comparator. 1. Rosenstock J, et al. Curr Med Res Opin. 2009;25:2401-2411. 2. Jadzinsky M, et al. Diabetes Obes Metab. 2009;11:611-622. 3. DeFronzo RA, et al. Diabetes Care. 2009;32:1649-1655. 4. Scheen AJ, et al. Diabetes Metab Res Rev. 2010;26:540-549. 5. Chacra AR, et al. Int J Clin Pract. 2009;63:1395-1406. 6. Hollander P, et al. J Clin Endocrinol Metab. 2009;94:4810-4819.

Sax=saxaglipUn; TZD=thiazolidinedione; PBO=placebo; Met=me\ormin; Sit=sitaglipUn; Gly=glyburide; A1C=glycated hemoglobin.

* P<0.0001 vs comparator. † P<0.0001 vs placebo and vs metformin 1000 mg twice daily. HD, high-dose metformin (1000 mg twice daily); LD, low-dose metformin (500 mg twice daily).

1. Del Prato S, et al. Diabetes Obes Metab. 2011;13:258-267. 2. Haak T, et al. Diabetes Obes Metab. 2012;14:565-574. 3. Gomis R, et al. Diabetes Obes Metab. 2011;13:653-661. 4. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65-74. 5. Gallwitz B, et al. Lancet. 2012;380:475-483. 6. Owens DR, et al. Diabet Med. 2011;28:1352-61.

Glucose Control with Linaglip6n Mono and Combina6on Therapy


Ini6al Combo w/ Mehormin 24 Weeks2

Ini6al Combo w/Pioglitazone 24 Weeks3


Add-‐on to Mehormin 2 Years5

Add-‐on to Mehormin + SU

24 Weeks6

N 503 791 389 700 1552 1055

Treatment PBO Lin Lin Met HD

Lin + Met LD

Lin + Met HD

Pio Lin + Pio

Met Lin + Met

Glim + Met

Lin + Met

Met + SU Lin + Met + SU

Baseline A1C (%)

8.0 8.0 8.7 8.5 8.7 8.7 8.6 8.6 8.0 8.1 7.7 7.7 8.1 8.2

Δ A

1C (%

)

* *

* *

† A1C=glycated hemoglobin; Lin=linaglipUn; Pio= pioglitazone; SU=sulfonylurea; PBO=placebo; Met=me\ormin; HD=high dose; LD=low dose; Glim=glimepiride.

1. DeFronzo RA, et al. Diabetes Care. 2008;31:2315–2317. 2. Rosenstock J, et al. Diabetes Care. 2010;33:2406–2408. 3. Nauck MA, et al. Int J Clin Pract. 2009;63:46-55.4. Pratley RE, et al. Diabetes Obes Metab. 2009;11:167-176. 5. Bosi E, et al. Diabetes Obes Metab. 2011;13:1088-1096. 6. Rosenstock J, et al. Diabetes Obes Metab. 2009;11:1145-1152.

Glucose Control with Aloglip6n Mono and Combina6on Therapy


Ini6al Combo w/ Pioglitazone 26 Weeks2


Add-‐on to Glyburide 26 Weeks4

Add-‐on to Met + Pio 52 Weeks5

Add-‐on to Insulin +/-‐ Met 26 Weeks6

N 329 655 527 500 803 390

Treatment PBO Alo Pio Alo Alo + Pio

Met Alo + Met

Gly Alo + Gly

Met + Pio

Alo + Met + Pio

Ins +/-‐ Met

Alo + Ins +/-‐ Met

Baseline A1C (%)

7.9 7.9 8.8 8.8 8.8 8.0 7.9 8.1 8.1 8.1 8.3 9.3 9.3

Δ A

1C (%

)

* * * *

*

*

* P<0.001 vs comparator(s).

A1C=glycated hemoglobin; Lin=linaglipUn; Pio=pioglitazone; SU=sulfonylurea; PBO=placebo; Met=me\ormin; HD=high dose; LD=low dose; Glim=glimepiride; mg=milligram; kg=kilogram; Alo=aloglipUn.

GLP-‐1 Receptor Agonists

Characteris6cs of GLP-‐1 Agonists Exena6de, Liraglu6de

Mechanism Mimic prolonged acUon of GLP-‐1

Efficacy Decrease A1C levels 0.5%–2.0% (depends on entry of glucose into bloodstream from gut)

Dosing Once-‐ or twice-‐daily injecUon*

Side effects Nausea, vomiUng, weight loss

Main risk C-‐cell thyroid tumors**, long-‐term safety unknown

Associated with PancreaUUs possible

Nathan DM, et al. Diabetes Care. 2008;31:173-175; Drucker DJ, et al. Lancet. 2006;368:1696- 1705. Exenatide [package insert]. San Diego, CA; Amylin Pharmaceuticals; 2010.

*Dosing depends on GLP-‐1 agonist **With liragluUde, in rodents only

A1C = glycated hemoglobin; GLP-‐1 = glucagon-‐like pepUde-‐1

Marketed GLP-‐1 Receptor Agonists

Characteris6c Exena6de BID Liraglu6de Exena6de ER IniUal U.S. approval 2005 2010 2012

Trade name Byeva® Victoza® Bydureon®

DescripUon

SyntheUc exendin-‐4, a pepUde idenUfied in H. suspectum; acUvates GLP-‐1 receptors and is resistant to DPP-‐4 degradaUon

GLP-‐1 modifieda to be resistant to DPP-‐4 degradaUon

ExenaUde contained in a hydrolyzable polymer microspheres for extended release

AdministraUon Subcutaneous injecUon

Half-‐life 2.4 hours 13 hours >1 week

Dosing 2× daily, before meals

1× daily, anyUme 1× weekly

a Amino acid substitution and addition of acyl chain.

1. Byetta (exenatide) [prescribing information]. 2. Victoza (liraglutide) [prescribing information]. 3. Bydureon (exenatide extended-release for injectable suspension) [prescribing information]. 4. Neumiller JJ. J Am Pharm Assoc. 2009;49(suppl 1):S16-S29. 5. DeYoung M, et al. Diabetes Technol Ther. 2011;13:1145-1154.

GLP-‐1=glucagon-‐like pepUde 1; GIP=gastric inhibitory pepUde; DPP-‐4=dipeptidyl peptidase-4; ER=extended release; BID=twice daily.

Δ A

1C (%

)

Glucose Control with Exena6de with/without Oral Agents

*P<0.001 vs comparator. †All exenatide dosages shown are 10 µg BID.

1. Moretto TJ, et al. Clin Ther. 2008;30:1448-1460 . 2. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. 3. Buse JB, et al. Diabetes Care. 2004;27:2628-2635. 4. Zinman B, et al. Ann Intern Med. 2007;146:477-485. 5. Kendall DM et al. Diabetes Care. 2005;28:1083-1091. 6. Heine RJ, et al. Ann Intern Med. 2005;143:559-569.



Add-‐on to Sulfonylurea 30 Weeks3

Add-‐on to TZD 16 Weeks4

Add-‐on to Mehormin + SU

30 Weeks5

Add-‐on to Met + SU vs Glargine 26 Weeks6

N 233 336 377 233 733 551

Treatment† PBO Exe Met Exe + Met

SU Exe + SU

TZD Exe + TZD

Met + SU

Exe + Met + SU

Glar + Met + SU

Exe + Met + SU

Baseline A1C (%) 8.2 8.2 8.7 8.6 7.9 7.9 8.5 8.5 8.3 8.2

* * * * * A1C=glycated hemoglobin; SU=sulfonylurea; PBO=placebo; Met=me\ormin; Exe=exenaUde; TZD=thiazolidinedione; Glar=glargine; BID=twice daily; ug=micro gram.

Δ W

eight (kg)

Weight Reduc6on with Exena6de Mono and Dual Combina6on Therapy

1. Moretto TJ, et al. Clin Ther. 2008;30:1448-1460 . 2. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. 3. Buse JB, et al. Diabetes Care. 2004;27:2628-2635. 4. Zinman B, et al. Ann Intern Med. 2007;146:477-485. 5. Kendall DM et al. Diabetes Care. 2005;28:1083-1091. 6. Heine RJ, et al. Ann Intern Med. 2005;143:559-569.





Add-‐on to Mehormin+SU 30 Weeks5

Add-‐on to Met + SU vs Glargine

26 Weeks6

N 233 336 377 233


SU Exe + SU

TZD Exe + TZD

Met + SU

Exe + Met + SU

Glar + Met + SU

Exe + Met + SU

* * * *

* **

*P<0.05 vs comparator. **P<0.0001 vs glargine. †All exenaUde dosages shown are 10 μg BID.

A1C=glycated hemoglobin; SU=sulfonylurea; PBO=placebo; Met=me\ormin; Exe=exenaUde; TZD=thiazolidinedione; Glar=glargine; BID=twice daily; ug=micro gram.

1.  Moretto TJ, et al. Clin Ther. 2008;30:1448-1460.

Δ S

ysto

lic B

P (m

mH

g)

Blood Pressure Changes with Exena6de

Monotherapy 24 Weeks

N 233

Treatment PBO Exe 10 μg BID

*

*P<0.05 vs placebo.

BP=blood pressure; PBO=placebo; Met=me\ormin; Exe=exenaUde; ug=micro gram; mmHg=millimeters of mercury.

1. Moretto TJ, et al. Clin Ther. 2008;30:1448-1460 . 2. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. 3. Buse JB, et al. Diabetes Care. 2004;27:2628-2635. 4. Zinman B, et al. Ann Intern Med. 2007;146:477-485.

Pat

ient

s R

epor

ting

Hyp

ogly

cem

ia (%

)

Hypoglycemia with Exena6de Mono and Dual Combina6on Therapy





N 233 336 377 233


SU Exe + SU

TZD Exe + TZD

A1C=glycated hemoglobin; SU=sulfonylurea; PBO=placebo; Met=me\ormin; Exe=exenaUde; TZD=thiazolidinedione; BID=twice daily; ug=micro gram. †All exenaUde dosages shown are 10 μg BID.

Exena6de: Adverse Events

Adverse Events*

Number (%) of Pa6ents

Monotherapy + Met and/or SU + TZD ± Met

Exe (n=155)

PBO (n=77)

Exe (n=963)

PBO (n=483)

Exe (n=121)

PBO (n=112)

Nausea 12 (8) 0 424 (44) 87 (18) 48 (40) 17 (15)

VomiUng 6 (4) 0 125 (13) 19 (4) 16 (13) 1 (1)

Diarrhea 125 (13) 29 (6) 7 (6) 3 (3)

Feeling jivery 87 (9) 19 (4)

Dizziness 87 (9) 29 (6)

Headache 87 (9) 29 (6)

Dyspepsia 5 (3) 0 58 (6) 14 (3) 8 (7) 1 (1)

Asthenia 39 (4) 10 (2)

GERD 29 (3) 5 (1) 4 (3) 0

Hyperhidrosis 29 (3) 5 (1)

*Occurring in ≥2% of paUents receiving exenaUde

1.  Byetta (exenatide) injection prescribing information. San Diego, CA: Amylin Pharmaceuticals, Inc. 2011.

SU=sulfonylurea; PBO=placebo; Met=me\ormin; Exe=exenaUde; TZD=thiazolidinedione.

1. Garber A, et al. Lancet. 2009;373:473-481. 2. Nauck M, et al. Diabetes Care. 2009;32:84-90. 3. Pratley RE, et al. Lancet. 2010;375:1447-1456. 4. Marre M, et al. Diabet Med. 2009;26:268-279. 5. Zinman B, et al. Diabetes Care. 2009;32:1224-1232. 6. Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055

Glucose Control with Liraglu6de with/without Oral Agents

Δ A1C

(%)

0.09 0.23

-‐0.24-‐0.51

-‐0.98 -‐0.9

-‐0.44 -‐0.5

-‐1.09-‐1.14 -‐1.00

-‐1.50

-‐1.13

-‐1.50-‐1.33

-‐2

-‐1.5

-‐1

-‐0.5

0

0.5

Monotherapy vs Glimepiride 52 Weeks1




Add-‐on to Met + TZD 26 Weeks5

Add-‐on to Met + SU 26 Weeks6

N 746 1091 665 1041 821 581

Treatment (mg/day)

Glim Lir Met Gli + Met

Lira + Met

Sit + Met

Lira + Met

SU Rosi + SU

Lira + SU

Rosi + Met

Lira + Rosi + Met

Met + SU

Glar + Met + SU

Lira + Met + SU

Baseline A1C (%)

8.4 8.3 8.4 8.4 8.4 8.5 8.4 8.4 8.4 8.5 8.4 8.6 8.3 8.2 8.3

* ** ** *

** ** *** *

*P<0.0001 vs monotherapy. **P<0.0001 vs dual therapy. ***P<0.01 vs glargine. †All liragluUde dosages shown are 1.8 mg QD.

A1C=glycated hemoglobin; Lir=liragluUde; Glim=glimepiride; SU=sulfonylurea; Rosi=rosiglitazone; Glar=glargine; Met=me\ormin; Exe=exenaUde; TZD=thiazolidinedione; QD=once daily; mg=milligram.

1. Garber A, et al. Lancet. 2009;373:473-481. 2. Nauck M, et al. Diabetes Care. 2009;32:84-90. 3. Pratley RE, et al. Lancet. 2010;375:1447-1456. 4. Marre M, et al. Diabet Med. 2009;26:268-278. 5. Zinman B, et al. Diabetes Care. 2009;32:1224-1230. 6. Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055.

Δ W

eigh

t (kg

)

Weight Reduc6on with Liraglu6de Mono and Dual Combina6on Therapy

* * * **

*

*

***







N 746 1091 665 1041 821 581

Treatment Glim Lir Met Glim + Met

Lira + Met

Sit + Met

Lira + Met

SU Rosi + SU

Lira + SU

Rosi + Met

Lira + Rosi + Met

Met + SU

Glar + Met + SU

Lira + Met + SU

* A1C=glycated hemoglobin; Lir=liragluUde; Glim=glimepiride; SU=sulfonylurea; Rosi=rosiglitazone; Glar=glargine; Sit=sitaglipUn; Met=me\ormin; Exe=exenaUde; TZD=thiazolidinedione; QD=once daily; mg=milligram.

*P<0.0001 vs glargine, rosiglitazone, sitaglip6n, or SU. **P<0.01 vs mehormin. ***P<0.05 vs SU. †All liragluUde dosages shown are 1.8 mg QD.

Blood Pressure Changes with Liraglu6de

Δ S

ysto

lic B

P (m

mH

g)

* *

* *




Add-‐on to Sulfonylurea 26 Weeks4,5



N 746 1091 665 1041 821 581

Treatment Glim Lir Met Glim + Met

Lira + Met

Sit + Met

Lira + Met

SU Rosi + SU

Lira + SU

Rosi + Met

Lira + Rosi + Met

Met + SU

Glar + Met + SU

Lira + Met + SU

1. Garber A, et al. Lancet. 2009;373:473-481. 2. Nauck M, et al. Diabetes Care. 2009;32:84-90. 3. Pratley RE, et al. Lancet. 2010;375:1447-1456. 4. Marre M, et al. Diabet Med. 2009;26:268-278. 5. Colagiuri S, et al. Diabetes. 2008;57(suppl 2): Abstr. 554-P. 6. Zinman B, et al. Diabetes Care. 2009;32:1224-1230. 7. Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055

A1C=glycated hemoglobin; Lira=liragluUde; Glim=glimepiride; SU=sulfonylurea; Rosi=rosiglitazone; SU=sulfonylurea; Glar=glargine; Sit=sitaglipUn; Met=me\ormin; Exe=exenaUde; TZD=thiazolidinedione; QD=once daily; mg=milligram.

*P<0.05 vs comparator. †All liragluUde dosages shown are 1.8 mg QD.

1. Garber A, et al. Lancet. 2009;373:473-481. 2. Nauck M, et al. Diabetes Care. 2009;32:84-90. 3. Pratley RE, et al. Lancet. 2010;375:1447-1456. 4. Marre M, et al. Diabet Med. 2009;26:268-278.

Hypoglycemia with Liraglu6de Mono and Dual Combina6on Therapy





N 746 1091 665 1041

Treatment† Glim Lira Met Glim + Met

Lira + Met

Sit + Met

Lira + Met

SU Rosi + SU

Lira + SU

*

Pat

ient

s R

epor

ting

Hyp

ogly

cem

ia (%

)

* *

*P<0.01 vs ac6ve comparator. †All liragluUde dosages shown are 1.8 mg QD.

A1C=glycated hemoglobin; Lira=liragluUde; Glim=glimepiride; Rosi=rosiglitazone; SU=sulfonylurea; Glar=glargine; Sit=sitaglipUn; Met=me\ormin; Exe=exenaUde; TZD=thiazolidinedione; QD=once daily; mg=milligram.

Liraglu6de: Adverse Events

Adverse Events*

Number (%) of Pa6ents Monotherapy + Me\ormin + Glimepiride + Met + TZD

Lir (n=497)

Glim (n=248)

Lir (n=724)

PBO (n=121)

Lir (n=695)

PBO (n=114)

Lir (n=355)

PBO (n=175)

Nausea 141 (28.4)

21 (8.5) 110 (15.2)

5 (4.1) 52 (7.5) 2 (1.8) 123 (34.6)

15 (8.6)

Diarrhea 85 (17.1) 21 (8.9) 79 (10.9) 5 (4.1) 52 (7.2) 2 (1.8) 50 (14.1) 11 (6.3)

VomiUng 54 (10.9) 9 (3.6) 47 (6.5) 1 (0.8) 44 (12.4) 5 (2.9)

ConsUpaUon 49 (9.9) 12 (4.8) 37 (5.3) 1 (0.9) 18 (5.1) 2 (1.1)

Headache 45 (9.1) 23 (9.3) 65 (9.0) 8 (6.6) 29 (8.2) 8 (4.6)

Dyspepsia 36 (5.2) 1 (0.9)

*Adverse events of interest occurring in ≥5% of paUents receiving liragluUde.

1.  Victoza (liraglutide) injection prescribing information. Princeton, NJ: Novo Nordisk Inc. 2012.

Lir=liragluUde; Glim=glimepiride; Rosi=rosiglitazone; Met=me\ormin; TZD=thiazolidinedione.

Nausea Declined Over Time with Liraglu6de Monotherapy

Pa6ents (%)

Liraglu6de Monotherapy vs SU

1. Liraglutide [package insert]. Princeton, NJ: Novo Nordisk Inc. 2010; 2. Garber A et al. Lancet. 2009;373:473-481.

SU=sulfonylurea; mg=milligram.

Long-Acting Release Technology

•  Exenatide (once-weekly): – Biodegradable polymeric microspheres

for extended release – Detectable plasma concentrations of

exenatide for weeks to months after a single dose Initial release Sustained release

hydration diffusion degradation erosion

Bartus RT et al. Science. 1998;281:1161-1162

M

1. Drucker DJ, et al. Lancet. 2008;372:1240-1250. 2. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258. 3. Bergenstal RM, et al. Lancet. 2010;376:431-439. 4. Diamant M, et al. Lancet. 2010;375:2234-2243. 5. Buse JB, et al. Lancet. 2013;381:117-124.

Glucose Control with Exena6de ER

Δ A

1C (%

)

Add-‐on to OAs*

30 Weeks1

Monotherapy vs OAs

26 Weeks2


Add-‐on to Met +/-‐ SU 26 Weeks4

Add-‐on to OAs†

26 Weeks5

N 258 820 514 456 911

Treatment Exe BID

Exe ER Sit Pio Met Exe ER Sit Pio Exe ER Glar + OAs

Exe ER + OAs

Lira + OAs

Exe ER + OAs

Baseline A1C (%)

8.3 8.3 8.5 8.5 8.6 8.5 8.5 8.5 8.6 8.3 8.3 8.4 8.5

P<0.001 P<0.0001 P<0.01

P=0.017 P=0.02 *Me\ormin, sulfonylurea, thiazolidinedione, or combinaUon of any 2 of these agents. †Me\ormin, sulfonylurea, me\ormin + sulfonylurea, or me\ormin + pioglitazone.

A1C=glycated hemoglobin; Pio=pioglitazone; Lira=liragluUde; SU=sulfonylurea; Glar=glargine; Sit=sitaglipUn; Met=me\ormin; Exe=exenaUde; ER=extended release; TZD=thiazolidinedione; BID=twice daily; mg=milligram; OA=oral agents.


Add-‐on to OAs*

30 Weeks1

Monotherapy vs OAs

26 Weeks2



Add-‐on to OAs†

26 Weeks5

N 258 820 514 456 911

Treatment (mg/day)

Exe BID


Exe ER + OAs

Lira + OAs

Exe ER + OAs

P<0.0001

Δ W

eigh

t (kg

)

Weight Reduc6on with Exena6de ER

P<0.001 P<0.001

A1C=glycated hemoglobin; Pio=pioglitazone; Lira=liragluUde; SU=sulfonylurea; Glar=glargine; Sit=sitaglipUn; Met=me\ormin; Exe=exenaUde; ER=extended release; TZD=thiazolidinedione; BID=twice daily; mg=milligram; OA=oral agents.

*Me\ormin, sulfonylurea, thiazolidinedione, or combinaUon of any 2 of these agents. †Me\ormin, sulfonylurea, me\ormin + sulfonylurea, or me\ormin + pioglitazone.


Add-‐on to OAs*

30 Weeks1

Monotherapy vs OAs

26 Weeks2



Add-‐on to OAs†

26 Weeks5

N 258 820 514 456 911

Treatment Exe BID


Exe ER + OAs

Lira + OAs

Exe ER + OAs

Pat

ient

s re

porti

ng

hypo

glyc

emia

(%)

Hypoglycemia with Exena6de ER

*Me\ormin, sulfonylurea, thiazolidinedione, or combinaUon of any 2 of these agents. †Me\ormin, sulfonylurea, me\ormin + sulfonylurea, or me\ormin + pioglitazone.

Pio=pioglitazone; Lira=liragluUde; SU=sulfonylurea; Glar=glargine; Sit=sitaglipUn; Met=me\ormin; Exe=exenaUde; ER=extended release; TZD=thiazolidinedione; BID=twice daily; mg=milligram; OA=oral agents.

Exena6de Extended Release: Adverse Events

Adverse Events*

Number (%) of Pa6ents

Monotherapy + Met + Met +/- SU

Exe ER (n=248)

Sit (n=163)

Pio (n=163)

Met (n=246)

Exe ER (n=160)

Sit (n=166)

Pio (n=165)

Exe ER (n=233)

Glar (n=233)

Nausea 28 (11.3) 6 (3.7) 7 (4.3) 17 (6.9) 39 (24.4) 15 (9.6) 8 (4.8) 30

(12.9) 3 (1.3)

Diarrhea 27 (10.9) 9 (5.5) 6 (3.7) 31

(12.6) 32

(20.0) 15 (9.6) 12 (7.3) 22 (9.4) 9 (4.0)

Injection site reaction

26 (10.5) 11 (6.7) 6 (3.7) 25

(10.2) 8 (5.0) 8 (4.8) 2 (1.2) 14 (6.0) 0

Constipation 47 (8.5) 4 (2.5) 3 (1.8) 8 (3.3) 10 (6.3) 6 (3.6) 2 (1.2)

Headache 20 (8.1) 15 (9.2) 13 (8.0) 30 (12.2) 15 (9.4) 15 (9.0) 9 (5.5) 23 (9.9) 18 (7.6)

Dyspepsia 18 (7.3) 3 (1.8) 8 (4.9) 8 (3.3) 8 (5.0) 6 (3.6) 4 (2.4)

Vomiting 18 (11.3) 4 (2.4) 5 (3.0)

Fatigue 9 (5.6) 1 (0.6) 5 (3.0)

*Adverse events of interest occurring in ≥5% of patients receiving exenatide extended release.

1. Bydureon (exenatide extended release) injection prescribing information. San Diego, CA: Amylin Pharmaceuticals, Inc. 2012.

Pio=pioglitazone; SU=sulfonylurea; Glar=glargine; Sit=sitaglipUn; Met=me\ormin; Exe=exenaUde; ER=extended release.

GLP-‐1 Receptor Agonist Safety: Nausea

•  Nausea is the most frequent adverse effect –  Affects as many as one-‐third of paUents –  Usually self-‐limiUng; however some paUents cannot tolerate these agents

•  Nausea may be decreased by: –  Avoiding overeaUng –  Slowing the UtraUon of exenaUde BID and liragluUde –  AdministraUng exenaUde BID closer to the start of a meal

1. Byetta PI 2013 2. Victoza PI 2013

GLP-‐1=glucagon-‐like pepUde 1; BID =two Umes daily

•  A personal or familial history of MTC or MEN2 are contraindicaUons for liragluUde and exenaUde due to the occurrence of c-‐cell tumors in rodents –  It is unknown if these agents cause c-‐cell tumors in humans as clinical

trials of humans were unable to determine relevance •  The value of rouUne calcitonin and/or ultrasound has not been

established –  These tests are not currently recommended –  Referral to an endocrinologist should be done for all paUents with

thyroid nodules or elevated serum calcitonin levels idenUfied for other reasons

•  It is advised that cases of MTC be reported to state cancer registry, regardless of treatment, in order to monitor potenUal associaUons

GLP-‐1 Receptor Agonist Safety: MTC Risk

Victoza Prescribing Information. 2013; Bydureon Prescribing Information. 2013; Parks M, et al. N England J Med. 2010;362:774-777.

MTC=medullary thyroid cancer; MEN2=mulUple endocrine neoplasia syndrome type 2

•  Clearance of exenaUde is affected by renal impairment, but not liragluUde.1,2 •  Renal funcUon may be decreased by hypovolemia secondary to nausea and

vomiUng.3

•  GLP-‐1 receptor agonist-‐associated renal impairment has been reported postmarkeUng

–  Most commonly associated with nausea, vomiUng, diarrhea, or dehydraUon –  May someUmes require hemodialysis

•  ExenaUde BID or ER is not recommended in paUents with severe renal impairment or end-‐stage renal disease

•  CauUon should be used in paUents with renal transplantaUon or moderate renal impairment

•  CauUon should be used when iniUaUng or escalaUng doses of liragluUde in paUents with renal impairment

1. Linnebjerg H. et al. Br J Clin Pharmacol. 2007;64:317-327. 2. Jacobsen L, et al. Br J Clin Pharmacol. 2009;68:898-905. 3. Byetta PI 2013. 4. Jacobsen L, et al. Br J Clin Pharmacol. 2009;68:898-905. 5. Weise WJ et al. Diabetes Care. 2009;32:e22-e23. 6. Ferrer-Garcia JC et al. Diabetes Med. 2010;27:728-729. 7. Lopez-Ruiz A, et al. Pharm World Sci. 2010;32:559-561.

GLP-‐1 Receptor Agonist Safety: Renal Impairment

GLP-‐1=Glucagon-‐like pepUde 1; BID =two Umes daily; ER=extended release.

•  PancreaUUs has been reported with DPP-‐4 inhibitors and GLP-‐1 receptor agonists, but a causal relaUonship has not been proven

•  It is important to educate paUents on the signs and symptoms of pancreaUUs

•  IncreUn-‐based therapies should be disconUnued if signs and symptoms arise

•  Therapy should not be resumed if pancreaUUs is confirmed

GLP-‐1 Receptor Agonist Safety: Pancrea66s

1. Ahmad SR, et al. N Engl J Med. 2008;358:1970-1971. 2. Garg R, et al. Diabetes Care. 2010;33:2349-2354. 3. Byetta PI 2013. 4. Victoza PI 2013. 5. Bydureon PI 2013. 6. Januvia PI 2013. 7. Onglyza PI 2013. 8. Tradjenta PI 2013. 9. Nesina PI 2013.

GLP-‐1=Glucagon-‐like pepUde 1; DPP-4=dipeptidyl peptidase-4.

Type 2 Diabetes and Pancrea66s Risk

There is a 2.8-‐fold increased risk of pancrea66s in pa6ents with type 2 diabetes

Inci

denc

e pe

r 100

,000

pa

tient

-yea

rs

Noel RA, et al. Diabetes Care. 2009;32:834-838.

Pancrea66s with Exena6de and Sitaglip6n Large Database Analysis

•  Analysis of data from large U.S. commercial health insurance database •  AcUve drug safety surveillance system •  June 2005 through June 2008 •  No increased risk for paUents treated with exenaUde (EXE) or sitaglipUn

(SIT), compared with me\ormin (MET) or glyburide (GLY)

Dore DD, et al. Curr Med Res Opin. 2009;25:1019-1027.

0.0 0.5 1.0 1.5 2.0 2.5

Relative risk (95% confidence interval)

EXE (n = 27,996) vs MET or GLY (n = 27,983)

SIT (n = 16,267) vs MET or GLY (n = 16,281)

Pancreatitis Occurrence 0.13% of EXE-treated patients

0.12% of SIT-treated patients

Sit=sitaglipUn; Met=me\ormin; Exe=exenaUde; Gly=glyburide.

PrevalenceofDiabetesandPrediabetes Update on Diabetes ...€¦ · Diabetes Care 2012;35:1364–1379...

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