Emerging Therapies and Treatment OptionsPhilip Raskin, MD

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Emerging!Therapies!and!Treatment!Options

Philip!Raskin,!MD,!FACP,!FACE,!CDEProfessor!of!Internal!Medicine

UT!Southwestern Medical!CenterDallas,!Texas!

Paradigm of!Treatment:!Treat to!Failure

Combo of oral agentsCombo of oral agents

Oral agents + insulinOral agents + insulin

InsulinInsulin

Oral agentOral agent

Diet and exercise

Progresion of disease

Emerging Therapies and Treatment OptionsPhilip Raskin, MD

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At insulin initiation, the average patient had:! 5 years with A1C >8%! 10 years with A1C >7%

Standard!Approaches!to!Therapy!Result!in!Prolonged!Exposure!to!Elevated!Glucose

Brown!JB!et!al.!Diabetes!Care.!2004;27:1535"1540.

Sulfonylurea or Metformin Monotherapy

AACE goal <6.5%

CombinationTherapy

Diet/Exercise

Mea

n A

1C a

t la

st v

isit

(%

)

YearsDiagnosis 2 3 4 5 6 7 8 9 10

9.6%

9.0%8.6%

6

7

8

9

10 Insulin

ADA goal <7%

Poor!Adherence!and!Persistence!Rates!!!!!in!Oral!Antidiabetic Therapy

Hertz RP, et al. Clin Ther. 2005;27:1064-1073.

No

nad

her

ence

(%

)

*Nonadherence = Medication Possession Ratio <80%†TZD=thiazolidinediones; SU=sulfonylureas; MET=metformin; AGI=!"glucosidase inhibitors; MEG=meglitinides.

Percentage of Adults 18-64 Years Old With Nonadherence,* by Therapeutic Class†

! Over 12 months:! 37% of patients

discontinued therapy

! 10.5% of patients failed to fill a second Rx for any hypoglycemic agent

! About 46% of patients were nonadherent.*

Emerging Therapies and Treatment OptionsPhilip Raskin, MD

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Lessons!from!the!UKPDS:!A1C

Years

Glycohemoglobin(A1C, %)

Intensive Group

Conventional Group

UKPDS. Lancet. 1998;352:837–853.

Inzucchi May 2012 Diabetes C

Emerging Therapies and Treatment OptionsPhilip Raskin, MD

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Definition!of!an!Incretin

• Released!during!nutrient!absorption

• Augments!insulin!secretion!at!physiologic!concentrations

• Insulinotropic effects!are!glucose!dependent

Creutzfeldt Wl. Diabetologia. 1979;16:75-85.

The!Incretins

Y A E G T F I S D Y S I A M D K I HQ

QDFVNWLLAQKGKKNDWK

H N QTI

GIP: Glucose-Dependent Insulinotropic Peptide

H A E G T F T S D V S S Y L E G Q AA

KEFIAWLVKGRG

GLP-1: Glucagon-Like Peptide–1

Amino acids shown in green are homologous with the structure of glucagon

Emerging Therapies and Treatment OptionsPhilip Raskin, MD

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Measurement!of!the!Incretin Effect

Glucose (mg/dL) Insulin (pmol/L)OGTT and Matched IV InfusionOGTT and Matched IV Infusion

Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-8.

GLP"1!Suppresses!Glucagon!Secretion75

50

25

0 30 60 90 120

SalineGLP-1

Infusion

Time, minutes

Glu

cago

n, p

g/m

L

Meal

Ahrén et al Diabetes Care. 2003;26:2860–2864.

Emerging Therapies and Treatment OptionsPhilip Raskin, MD

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Decreased!Postprandial!Levels!of!!GLP"1!in!Patients!With!Type!2!Diabetes

* * * * ** *

*P<0.05, Type 2 diabetes vs NGT. Toft-Nielsen MB et al. J Clin Endocrinol Metab. 86: 3717, 2001

Meal Started

Meal Finished

(10-15)

Comparison!of!Physiology!of!GLP"1!and!GIP

GLP-1 GIP

Site of production L-cells in ileum and colon

K-cells in duodenum and

jejunum

Response to stimuli Indirect/neuronal Direct

Inhibits glucagon Yes No

Slows gastric emptying Yes No

Stimulation of #-cell growth/mass Yes Yes

Major target tissues#-cell, !-cell,

stomach, nervous system

#-cell, adipose tissue

Antagonist Exendin [9-39] GIP [7-30]

Emerging Therapies and Treatment OptionsPhilip Raskin, MD

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GLP"1!and!GIP!Are!Degraded!by!the!DPP"4!Enzyme

Meal

Intestinal GIP and GLP-1 release

GIP and GLP-1 Actions

DPP-4Enzyme

GIP-(1–42)GLP-1(7–36)

Intact

GIP-(3–42)GLP-1(9–36)Metabolites

Rapid Inactivation

Half-life*GLP-1 ~ 2 minutes

GIP ~ 5 minutes

What!is!DPP"4?" A serine protease widely distributed throughout

the body

" Cleaves N-terminal amino acids and inactivates a number of biologically active peptides, including the incretins GLP-1 and GIP

" DPP-4 effects on GLP-1 and GIP play a key role in incretin activity and glucose homeostasis" Inactivates GLP-1 >50% in ~1–2 min

" Inactivates GIP >50% in ~7 min

Emerging Therapies and Treatment OptionsPhilip Raskin, MD

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Novel!Therapies:!GLP"1!Mimetics

Improve!metabolic!control!by!several!mechanisms

• Stimulate!insulin!secretion!without!causing!!hypoglycemia!

• Promote!weight!loss!rather!than!causing!weight!gain!

• Reduce!post"prandial glucagon!secretion!(paradoxically!increased!in!diabetic!patients)

Drucker DJ, Nauck MA. Lancet. 2006;368:1696-1705.

2!Different!Approaches!to!Enhance!GLP"1!

98

GLP-1 secretion is impaired in patients with T2DM

Injectable GLP-1 RAs with longer half-life, providing supraphysiologic GLP-1:• Exenatide twice daily• Liraglutide• Exenatide long-acting

release

Oral DPP-4 inhibitors inhibit the actions of DPP-4, reduce degradation of existing GLP-1, providing physiologicGLP-1 concentrations: • Alogliptin• Linagliptin• Sitagliptin• Saxagliptin

$ GLP-1 concentration

Emerging Therapies and Treatment OptionsPhilip Raskin, MD

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Actions!of!DPP"4!Inhibitors!and!GLP"1!RAs!in!Regulating!Glucose!Homeostasis

Satiety and weight loss

% Gastric emptying

$ Insulin secretion

DPP-4 inhibitors

GLP-1 RAs

Physiologic Supraphysiologic/Pharmacologic

Progressive GLP-1R Activation

GLP

-1R

–Dep

ende

nt A

ctio

ns

GLP-1R = GLP-1 receptor. Holst JJ, et al. Trends Molec Med. 2008;14:161-168.

% Glucagon secretion

GLP"1!Receptor!Agonists

Emerging Therapies and Treatment OptionsPhilip Raskin, MD

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• In general, liraglutide 1.8 mg once daily provides greater glycemic control vs exenatide 10 mcg twice daily (LEAD-6)1

- Mean A1C reductions with liraglutide: 1.1%-1.6% (mono- and combination therapy)2

- Mean A1C reductions with exenatide twice daily: 0.7%-1.0% (mono- and combination therapy)2

• Exenatide long-acting release provides greater glycemic control vs exenatide BID (-1.6 ± 0.1% vs -0.9 ± 0.1%, DURATION-5)3

GLP"1!Receptor!Agonists

1. Buse JB, et al. Lancet. 2009;374:39-47; 2. Mundil D. Diab Vasc Dis Res. 2012;9:95-108; 3. Blevins T, et al. J Clin Endocrinol Metab. 2011;96:1301-1310.

DURATION = Diabetes Therapy Utilization: Researching Changes in A1C, Weight, and Other Factors Through Intervention with Exenatide Once Weekly; LEAD = Liraglutide Effect and Action in Diabetes.

Glycemic!Effects

• GLP-1Rs are not restricted to the pancreas; therefore, GLP-1 RAs cause additional nonglycemic effects:• Improvements in beta-cell function• Reduction in Food intake• Renal, GI, neuroprotective • Improvements in markers of cardiovascular risk

• ? Cardiovascular biomarkers (PAI-1, BNP, hs-CRP)• Reduction in oxidative stress• Weight, SBP, lipids

Vilsbøll T, Garber AJ. Diabetes Obes Metab. 2012;14:41-49.

BNP = B-type natriuretic peptide; hs-CRP = high-sensitivity C-reactive protein; PAI-1 = plasminogen activator inhibitor-1; SBP = systolic blood pressure.

Nonglycemic!Effects

Emerging Therapies and Treatment OptionsPhilip Raskin, MD

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GLP"1!Receptor!Agonists

• Causes increased insulin secretion by increasing first phase secretion

• Decreases glucagon secretion• Slows gastric emptying• Decreases food intake (mediated through CNS)

1. Fehse F, et al. J Clin Endocrinol Metab. 2005;90:5991-5997.2. Kolterman OG, et al. J Clin Endocrinol Metab. 2003;88:3082-3089.3. Maekawa F, et al. J Neuroendocrinol. 2006;18:748-756.4. Rachman J, et al. Diabetes. 1996;45:1524-1530.

Mechanisms!of!action

Drug Half"Life

Administration!and!Dosage

FDA!approved!with!basal!insulin

Exenatide 2"4!hours

5!or!10!mcg!twice/day Yes

Liraglutide12"14!hours 1.2!or!1.8!mg!

once/day Yes

Exenatide!!!LAR

>!1!week

2.0!mg!once/week No

Overview!of!GLP"1!Receptor!Agonists!

Emerging Therapies and Treatment OptionsPhilip Raskin, MD

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Weight!Reduction!With!GLP"1!RAs:!Summary!of!Clinical!Trial!Data

aBackground oral antihyperglycemic agent(s).MET = metformin.

-4.0-3.5

-6.2

-3.5 -3.9

-5.5

-0.4

-6.2

-4.0 -4.4

-7.0

-5.1

-8.1

-5.1-5.7

-9.0-8.0-7.0-6.0-5.0-4.0-3.0-2.0-1.00.0

Cha

nge

in W

eigh

t (lb

)

+ None1,2,a + SU1 + MET1 + SU/MET1 + TZD ! MET1 + MET ! SU1

Exenatide 10 mcg twice dailyLiraglutide 1.8 mg once dailyExenatide 2 mg every week

1. Mundil D. Diab Vasc Dis Res. 2012;9:95-1082. Poon T, et al. Diabetes Technol Ther. 2005;7:467-477.

GLP"1!Receptor!Agonists:!Place!in!Therapy!• At!any!time!when!target!A1C!is!not!being!achieved

• As!monotherapy• As!combination!therapy

• In!2"drug!combinations!with!metformin• In!3"drug!combinations• In!combination!with!basal!insulin!(Exenatide!and!Liraglutide)

• When!certain!goals!are!preferred!• When!hypoglycemia!is!particularly!undesirable• When!minimizing!weight!gain/weight!reduction!is!an!important!consideration

• When!actions!complement!those!of!other!antihyperglycemic!agents

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

Emerging Therapies and Treatment OptionsPhilip Raskin, MD

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Risk!for!Pancreatitis!With!GLP"1!RAs!

• Pancreatitis risk is 1.5- to 3-fold higher in patients with T2DM• Increased risk is independent of T2DM therapy

• Literature suggests no proven causal relationship between GLP-1 RAs or DPP-4 inhibitors and pancreatitis

• In June 2013, the National Institutes of Health completed a review of the known data suggesting an association between incretin therapy and pancreatic disease

• Data did not support a relationship between incretin agents and pancreatic disease

Noel RA. Diabetes Care. 2009;32:834-838; Gonzalez-Perez A. Diabetes Care. 2010;33:2580-2585;Nauck M. Diabetes Care. 2013;36:2126-2132; American Diabetes Association. http://www.diabetes.org/for-media/2013/recommendations-for.html. Accessed October 14, 2013.

Risk!for!Pancreatitis!With!GLP"1!RAs!(cont’d)

• ADA/EASD/IDF statement:

• “At this time, there is insufficient information to modify current treatment recommendations. No patient should discontinue medication without first consulting with their health care provider. Their health care provider should take into account the patient’s therapeutic responses and adverse events when considering whether to maintain or alter established therapy.”

• If pancreatitis is suspected:• Discontinue GLP-1 RA, perform confirmatory tests, and treat

appropriately• Do not restart GLP-1 RA if pancreatitis is confirmed

• If patient has a history of pancreatitis, consider other antihyperglycemic therapies

IDF = International Diabetes Federation. American Diabetes Association. http://www.diabetes.org/for-media/2013/recommendations-for.html. Accessed October 14, 2013; Nainggolan L. www.medscape.com/viewarticle/779851. Accessed October 14, 2013; Byetta [package insert]. San Diego, CA: Amylin Pharmaceuticals, LLC; February 2013.

Emerging Therapies and Treatment OptionsPhilip Raskin, MD

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• Currently unknown whether GLP-1 RAs increase thyroid cancer risk

• Liraglutide and exenatide once weekly are contraindicated in patients with a personal or family history of medullary thyroid carcinoma or with multiple endocrine neoplasia syndrome type 2

C"Cell!Thyroid!Cancer!Risk!With!GLP"1!RAs

Chia WY. Exp Diabetes Res. 2012;2012:924168; Bydureon [package insert]. San Diego, CA: Amylin Pharmaceuticals, LLC; January 2012; Victoza [package insert]. Princeton, NJ: Novo Nordisk Inc., April 2012.

DPP"4!inhibitors

Emerging Therapies and Treatment OptionsPhilip Raskin, MD

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DPP"4!inhibitors

– Sitagliptin– Saxagliptin– Linagliptin– Alogliptin

• Monotherapy• Adjunct to diet and exercise to improve glycemic

control in patients with type 2 diabetes mellitus

• Combination therapy• To improve glycemic control in combination with other

oral hypoglycemic agents when the single agent alone with diet and exercise does not provide adequate glycemic control

• Sitagliptin approved for use with insulin

• Important limitations of use• DPP-4 inhibitors should not be used in patients with

type 1 diabetes or for the treatment of diabetic ketoacidosis

DPP"4!Inhibitors!Indications!

Emerging Therapies and Treatment OptionsPhilip Raskin, MD

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DPP"4!Inhibitors:!Benefits!and!Risks

• Lower by 0.5 to 0.9% HbA1c• Low risk of hypoglycemia as monotherapy or

when used with metformin • Weight neutral

• Hypoglycemia risk when given with SU’s or insulin• Pancreatitis: new safety data shows no

relationship to pancreatic cancer or pancreatitis

Risks and Adverse Events

Benefits

Garber, Endocrine Practice 19: (Suppl 1)1, 2013Scirica, et al NEJM 369:1317, 2013White, et al NEJM 369:1327, 2013

SGLT!2!Inhibitors

Emerging Therapies and Treatment OptionsPhilip Raskin, MD

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SGLT!2!Inhibitors

• Canaglifozin• Dapaglifozin

SGLT!2 Inhibitors

• Blocks the Sodium-Glucose Co-transporter -2 in the proximal tubule in the kidney, resulting in increase glycosuria and a decrease in blood glucose levels

• Is independent of insulin or insulin secretion• Ineffective in individuals with reduced renal

function

Mechanisms!of!action

Emerging Therapies and Treatment OptionsPhilip Raskin, MD

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SGLT!2!Inhibitors:!Benefits• Lower HbA1c by 0.4 - 0.9%• Reduce weight by 3-4 Kg• Reduce Systolic blood pressure by 5-6

mm Hg• Low risk of hypoglycemia• No increased CV Risk (studies ongoing)

Garber, et al Endocrine Practice 19 (Suppl1):1,1013Abdul-Ghani, et al Endocr Rev 32:515, 2011Tahrani and Barnett Daibetes Ther 1:45, 2010Stenlof, et al Daibetes Obes Metab 15:372, 2013Whaley Diabetes Metab Syndr Obes 5:135, 2012Foote, et al Diabetes Vasc Dis Research 9:117, 2012

Emerging Therapies and Treatment OptionsPhilip Raskin, MD

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SGLT!2!Inhibitors:!Risks!and!Adverse!Effects

• Main adverse effects– Genitourinary tract infections, mainly genital

• Safety Concerns– Volume depletion/orthostatic hypotension

• Less HbA1c reduction in patients with Stage 3 CKD; not recommended for those with stage 4-5 CKD

• Cardiovascular safety studies show no increased CV risk

US FDA Briefing Document NDA 202293, 2011US FDA Briefing Document NDA 204042, 2013

Summary

• Incretin hormones reverse some of the key problems in the pathophysiology of type 2 diabetes

• GLP-1receptor agonists and DPP-4 inhibitors improve glucose control without weight gain or hypoglycemia and GLP-1 receptor agonists may also cause weight loss in many patients

• SGLT 2 Inhibitors improve glucose control without hypoglycemia and can lead to weight loss

• Insulin, while still the gold standard for the treatment of Type 2 diabetes, does not have a significant effect on the alpha cell, plus it can cause hypoglycemia and weight gain