New Therapies in T2DM: Finally Moving in Directions We Need!

James Gavin, III, MD, PhD CEO & Chief Medical Officer, Healing Our Village, Inc.

Clinical Professor of Medicine Emory University, School of Medicine

Atlanta, Georgia USA

The Global Profile of the Diabetes Epidemic is

Nothing Short of Frightening!

Distribution of diabetes worldwide: 2014 estimates

Numbers indicate millions of patients with T1D or T2D according to IDF Diabetes Atlas 2014 updates. Available at http://www.idf.org. Accessed February 2015

The worldwide challenge of glycaemic control!

Mean HbA1C in T2D

IDF Diabetes Atlas 2014 updates. Available at http://www.idf.org Accessed February 2015 1. Lopez Stewart G et al. Rev Panam Salud Publica 2007;22:12–20; 2. Kostev K & Rathmann W. Primary Care Diabetes 2013;7:229–233; 3. Oguz A et al. Curr Med Res Opin 2013;29:911–920; 4. Ko SH et al. Diabet Med 2007;24:55–62; 5. Arai K et al. Diabetes Res Clin Pract 2009;83:397–401; 6. Harris SB et al. Diabetes Res Clin Pract

2005;70:90–97; 7. Hoerger TJ et.al. Diabetes Care 2008;31:81–86; 8. Liebl A et al. Diabetes Ther 2012;3:e1–10; 9. Shah S et al. Adv Ther 2009;26:325–335; 10. Blak BT et al. Diabet Med 2012;29:e13–20; 11. Valensi P et al. Int J Clin Pract 2008;62:1809–1819

“A threat to families, member states

and the entire world”___

UN General Assembly, 2002

0

100

200

300

400

500

600

700

80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04

Year of entry

People with diabetes (n)

ORGAN FAILURE: NUMBER OF PEOPLE WITH DIABETES ENTERING THE AUSTRALIAN DIALYSIS REGISTER 1980-2004

Source: Disney A. Australia and New Zealand transplant registry, 2002

DEATHS ATTRIBUTABLE TO DIABETES AS PERCENTAGE OF ALL DEATHS IN THE TOP 10 COUNTRIES FOR DIABETES PREVALENCE (20-79 AGE GROUP), 2007

0 5 10 15 20 25 30 35 40 45

Mexico

Egypt

Mauritius

Tonga

Oman

Kuwait

Bahrain

Saudi Arabia

United Arab Emirates

Nauru

MalesFemales

Percentage of all deaths (%)

National Diabetes Information Clearinghouse. At: http://www.niddk.nih.gov/health/diabetes/pubs/dmstats/dmstats.htm.

Long-term Complications of Diabetes Consequences of Sustained Hyperglycemia

Diabetic Retinopathy

Leading cause of blindness

in working age adults

Diabetic Neuropathy

Leading cause of nontraumatic lower extremity amputations

Diabetic Nephropathy

Leading cause of end-stage renal disease

Stroke

Cardiovascular Disease

2-fold to 4-fold increase in

cardiovascular events and mortality

Del Prato S, et al. Int J Clin Pract 2010;64:295–304.

6.5

6.0

7.0

7.5

8.0

9.5

9.0

8.5

1 2 3 4 5 6 7 8 10 9 12 11 14 13 15 17 16 Time since diagnosis (years)

Before entering VADT intensive treatment arm After entering VADT intensive treatment arm

HbA

1c (%

) Generation of a ‘bad

glycemic legacy’ Drives risk of complications

Modelling the prior history of patients recruited in VADT

illustrates the drawbacks of late

intervention

Solid line: changes in HbA1c in response to intensive treatment in VADT

Upper broken line: theoretical reconstruction of prior diabetes progression based on UKPDS

Lower broken line: the ideal time course of glycemic control

Legacy of ‘Bad Metabolic Memory’

WHAT ARE WE MISSING IN THE TREATMENT OF T2DM?---WHY ARE OUTCOMES STILL SO POOR?

We have not met the obesity challenge We have not achieved glucose and other key targets

We have failed to address pathophysiology of disease

We have not been assertive in advancing therapy or controlling important cardiometabolic risk factors

We have inadequately used early combination Rx We fail to routinely apply standards and guidelines How can we now meet these unmet needs?

General Considerations for Addressing the Range of Unmet Needs

Refresh/expand our understanding of diabetes pathophysiology Understand implications of disease natural history

Understand implications of disease heterogeneity Understand the singular urgency for individualization of therapy Understand the capabilities/limitations of current

tools/treatments Understand the shortcomings of current treatments and the

urgency for newer treatment approaches

Treatment that is disease-modifying

Treatments that are effective independent of beta cell status, and thus indifferent to disease stage

Treatments that avoid weight gain or promote weight loss

Treatments that minimize the risk of hypoglycemia

Treatments that are neutral or beneficial in their impact on other CV risk factors

Treatments that are easily and reliably used by patients in a sustainable fashion (improved adherence/concordance)

“Major Needs” in Current Therapy for T2DM

Years of Diabetes

Del Prato S et al. Diabetologia. 2009;52(7):1219–1226. T2DM = type 2 diabetes mellitus.

Natural History: T2DM Is a ProgressiveDisease

13

250

200

150

100

50

0

250

200

150

100

50

300

350

0 –5 –10 5 10 15 20

20 30

Rela

tive

Func

tion

(%)

Glu

cose

(

mg/

dL)

Post-meal glucose

Fasting glucose

Insulin resistance

Beta-cell function

52.2

27.5

79.1

56.8 51.3

77.7

14.3

72

51.4

12.6

0

20

40

60

80

100Pa

tient

s with

diab

etes

(%

)

n=1444 n=1342

Goal Achievement in Diabetes

*Data from separate studies. BP = blood pressure; LDL-C = low-density lipoprotein cholesterol; NHANES = National Health and Nutrition Examination Survey. Ali MK et al. N Engl J Med. 2013;368:1613-1624. Stark Casagrande S et al. Diabetes Care. 2013;36:2271-2279.

NHANES 2007-2010*

<7 <8 >9 <70 <100 A1c (%)

LDL-C (mg/dL)

BP (mm/Hg)

<130/80 Nonsmoker All goals met Taking

a statin BP

(mm/Hg)

<140/90

The Complexity in the Natural History of Type 2 Diabetes Defies a Simplistic Treatment Approach

IR phenotype Atherosclerosis

Obesity, Hypertension, ↓HDL, ↑TG,

HYPERINSULINEMIA

Endothelial dysfunction PCO,ED

Environmental factors; Other Diseases

Obesity (visceral)

Poor Diet Inactivity

Insulin Resistance

Risk of Dev. Complications

Courtesy of S. Schwartz, MD

ETOH BP

Smoking

Eye Nerve Kidney

↓ Beta Cell Secretion

Genes

Blindness Amputation

CRF

Disability

Disability

MI CVA Amp

Age 0-15 15-40+ 15-50+ 25-70+

Macrovascular Complications

IGT – OMINOUS OCTET Type 2 DM 8 mechanisms of hyperglycemia

Microvascular Complications

DEATH

Clinical Inertia Results in Prolonged Exposure to Hyperglycemia

Brown JB, et al. Diabetes Care. 2004;27(7):1535-1540.

At insulin initiation, the average patient had • 5 Years with HbA1c >8%

• 10 Years with HbA1c >7%

10

7

Mea

n H

bA1c

(%)

9

8

Sulfonylurea or metformin

monotherapy

ADA goal ≤7%

Combination therapy

Diet/exercise

9.6%

Insulin

9.2% 9.2%

7.2% 7.4% 7.7%

Glucose reabsorption

Glucagon secretion α

Better Understanding of the Pathophysiology of Type 2 Diabetes has Resulted in Newer Treatments of the Defects

DeFronzo RA. Diabetes. 2009;58:773-795..

Hyperglycemia

Insulin secretion β

Glucose production

Lipolysis Neurotransmitter

function

Incretin effect

Glucose uptake

Glucose reabsorption

1. Rodbard H, et al. Endocr Pract. 2009;15:540-559; 2. Drucker D, et al. Diabetes Care. 2010;33:428-433.

Noninsulin T2DM Agents: Disease Complexity Drives Need for Complementary Actions

Action Met

form

in1

SUs1

Glin

ides

1

TZD

s1

AGIs1

GLP

-1 R

As1,

2

DPP

-4

inhi

bito

rs1

SGLT

-2 In

hib

↑ Insulin secretion

↑ Insulin sensitivity/action

↓ Hepatic glucose production

↓ Gastric emptying/glucose absorption

↑ Satiety

Weight ↓ ↑ ↑ ↑ 0 ↓↓ 0 ↓↓

Glucose-lowering

It is not just the complexity, but in addition, the heterogeneity of

diabetes that has magnified the difficulty of effective and

sustainable treatment regimens

Years from diagnosis

Insulin Sensitivity

0 0

40

20

2 4 6

60

Heterogeneity of T2DM Within Populations: the Belfast Diet Study

Levy J, et al. Diabet Med. 1998;15(4):290-296.

2–4 years 5–7 years 8–10 years

Time to need glucose-lowering medication

β-Cell function

(%)

0 0

60

40

20

2 4 6

*β-cell function determines onset and progression of secondary dietary failure in DM2

Diabetes in USA insulin resistance

Diabetes in Asia impaired insulin

secretion

4

0.55

0 Caucasian

(Welch)

｝ Japanese

(Taniguchi)

Insulin Sensitivity Insulin Secretion

0

20

40

60

80

100

80 120 160 200 FBS (mg/dl)

US Caucasian (DeFronzo)

Japanese (Seino)

Heterogeneity in T2DM exists!

Clinical characteristics of T2DM in Asia

Majority of Japanese type 2 diabetes is non-obese (average BMI <24) ( Y Seino, N

Yamada)

Non-obese but visceral adiposity (Y Matsuzawa; T Kadowaki)

Decreased ß cell mass (KH Yoon)

Impaired insulin secretion occurs at early

stage or even before onset of diabetes (Y Seino, DJ Kim)

Only 1/2 in Japanese and 1/4 in Korean

diabetes appear to have insulin resistance (Y Seino, SA Chang)

What’s the Evidence that Heterogeneity in Type 2 Diabetes exists that may demand Different Treatments ?

Heterogeneity of Diabetes: Key Lessons

Differences in disease behavior occur both within and across populations

There is a complex/changing underlying pathophysiology in T2DM---with a common element of toxicity!

There is no “one size fits all” approach to therapy There is urgency for individualization of treatment For adequate treatment approaches, we need tools and therapies

with wide-ranging capabilities, including tools that reduce glucose toxicity independent of defects

We urgently need NEW TOOLS with different and wide-ranging capabilities!

Evolution of Pharmacotherapy for T2DM

Bromocriptine/ Colesevelam 9

Num

ber o

f uni

que c

lasse

s

1950 1960 1970 1980 1990 2000 2010

8

7

6

5

4

3

2

1 Insulin

Metformin

10/11

GLP-1 Receptor Agonists

Pramlintide DPP-4 Inhibitors

α-glucosidase inhibitors

Thiazolidinediones

Repaglinide, Nateglinide

SFUs - Glipizide, Glyburide, Glimepiride

Qaseem A et al. Ann Intern Med. 2012;156:218-231.

12 SGLT2 inhibitor Next???

HYPERGLYCEMIA

Pharmacological Actions of Diabetes Drugs*

Skeletal Muscle Insulin Sensitivity TZDs

Liver

Hepatic Glucose Production Metformin GLP-1 agonists DPP-4 inhibitors

Pancreas Insulin Secretion Sulfonylureas Glinides GLP-1 agonists DPP-4 inhibitors

Intestine

GI Motility/Satiety/CHO uptake GLP-1 agonists Alpha Glucosidase Inhibitors

*Other than insulin

Glucagon Suppression GLP-1 agonists DPP-4 inhibitors

Brain

Kidney Glucosuria

SGLT2 inhibitors

Sympatholytic, Circadian Rhythm Bromocriptine QR

Reduction of Glucose Toxicity: an Early and Urgent Priority of T2DM Treatment!

Multiple pathways must be leveraged to reduce the glucose burden!

Reduction of food intake is a direct approach Reduction of gluconeogenesis is an indirect path Glucosuria is a direct approach Reduction of gut uptake is a direct approach Thus, kidney and gut have become more appealing new

targets for novel treatment approaches in T2DM

The emergence of deeper understanding of diabetes

pathophysiology has driven the quest for new targets of treatment and thus new tools for treatment

of this disease!

1

2

3

Existing agents all work via Insulin-dependent mechanisms to reduce hyperglycemia in T2DM and are known to have limitations that may not

apply to organs like Gut and Kidney

Insulin action • Thiazolidinediones

• Metformin

Insulin release • SUs

• GLP-1R agonists* • DPP4 inhibitors*

• Meglitinides

Insulin replacement • Insulin

Glucose utilisation

Adipose tissue, muscle and liver

Pancreas

*In addition to increasing insulin secretion, which is the major mechanism of action, GLP-1R agonists and DPP4 inhibitors also act to decrease glucagon secretion.

DPP4, dipeptidyl peptidase-4; GLP-1R, glucagon-like peptide-1 receptor; SUs, sulphonylureas. 1. Washburn WN. J Med Chem 2009;52:1785–94; 2. Bailey CJ. Curr Diab Rep 2009;9:360–7; 3. Srinivasan BT, et al. Postgrad Med J 2008;84:524–31;

4. Rajesh R, et al. Int J Pharma Sci Res 2010;1:139–47.

Holst JJ, et al. Diabetes. 2004;53(suppl 3):s197-s204; Meier JJ, et al. Diabetes Metab Res Rev. 2005;21:91-117.

“The Gut as Treatment Target: What Is Incretin Therapy?”

Incretins are gut-derived hormones: Secreted in response to nutrients that potentiate insulin secretion and

suppress glucagon secretion (gut serves as a “relay station”) Mediates the signal between food ingestion and postmeal glucose and

lipid control (specialized cells strategically-located for this function) Act in a glucose-dependent fashion

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

Rapidly inactivated by dipeptidyl peptidase 4 (DPP-4)

Incretin Effect

The Incretin Effect Is Reduced in Type 2 Diabetes Patients

Nauck M, et al. Diabetologia. 1986;29:46-52.

IV Glucose

Time (min)

Oral Glucose (50 g) Pl

asm

a G

luco

se (m

M)

0

5

10

15

0 60 120 180

Plas

ma

Insu

lin (m

M)

0

0.1

0.2

0.3

0.4

0.5

0.6

0 60 120 180 Time (min)

Healthy Subjects

Plas

ma

Insu

lin (m

M)

* * *

0

0.1

0.2

0.3

0.4

0.5

0.6

0 60 120 180 Time (min)

Diabetic Patients

Glucose-Insulin Dynamics in Incretin Action in T2DM

Okerson T, et al. Cardiovasc Ther. 2012;30:146-155.

Impact of Incretin-based Therapies: Important Distinctions

GLP-1 RAs – slow gastric emptying, increase satiety, promote weight reduction, improve cardiovascular risk factors, may improve beta cell mass and function (animal models only), now listed in new AACE guidelines as a treatment option in patients with prediabetes (currently off-label). Preferred treatment but only available via s.q. injection. (corrects incretin defect extra-intestinally via direct enhancement of plasma levels)

DPP-4 inhibitors – weight neutral, taken orally, generally well tolerated (corrects incretin defect at gut site of the defect)

The mechanism of correction is glucose and insulin- dependent, a potential limitation across the natural history of T2DM

Cardiovascular Safety Considerations for DPP-4 Inhibitors in Patients with T2DM

Recent meta-analysis affirms no increased risk of mortality, MI, or stroke with DPP-4 inhibitors4,b

US FDA advisory committee – new labeling information regarding potential HF risk with alogliptin and saxagliptin, but CV safety profile is acceptable5

Long-term CV safety trials are in progress for linagliptin6

Trial description Risk of major CV events HF

Alogliptin (EXAMINE: n = 5390; median follow-up, 18 months)1 No increased riska Equivocal risk

Saxagliptin (SAVOR: n = 16,492; median follow-up, 2.1 years)2 No increased riska More hospitalizations

(P = .007)

Sitagliptin (TECOS: n = 14,724; median follow-up, ≈ 3 years)3 No increased riska No increased risk

a Primary endpoint: composite of death from CV causes, nonfatal MI, nonfatal stroke, unstable angina (sitagliptin)

b 94 RCTs for alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin vs PBO or active control (n=85,244; 29 weeks of median follow-up)

1. White WB et al. N Engl J Med. 2013;369:1327-1335. 2. Scirica BM et al. N Engl J Med. 2013;369:1317-1326. 3. Results from TECOS. Presented at the ADA 75th Scientific Sessions. Available at: professional.diabetes.org/presentations_details.aspx?session=4723. 4. Savarese G et al. Int J Cardiol. 2014;181C:239-244. 5. MedPage Today. Available at: www.medpagetoday.com/Cardiology/Diabetes/51003. 6. ClinicalTrials.gov. Available at: clinicaltrials.gov/ct2/results?term=linagliptin+stroke&Search=Search.

Agent – Trial Titlea Status of Long-Term CV Safety Trials in Populations at Increased Risk for CV Events

Lixisenatide – ELIXA2,3 Completed 2/2015b – non-inferior to PBO for CV safety3,c

Liraglutide – LEADER2 Anticipated completion 10/20152

Exenatide QW – EXSCEL2 Anticipated completion 4/20182

Dulaglutide – REWIND2 Anticipated completion 4/20192

Cardiovascular Safety of GLP-1 RAs

Recent meta-analysis of CV risk1 ALBI, EXN BID, EXN QW, LIRA, and TASPO trials

Short-terma trials of individuals with low CV risk

No increased risk of major adverse cardiovascular event (MACE), acute MI, stroke, all-cause mortality, or CV death vs comparators

a Most trials 24-52 weeks. b Complete results to be presented at 2015

ADA Scientific Sessions. c Time to first MACE.

1. Monami M et al. Diabetes, Obes, Metab. 2014;16:38-47. 2. ClinicalTrials.gov. Available at: www.clinicaltrials.gov. 3. Sanofi press release. Available at: www.news.sanofi.us/2015-03-19-Sanofi-Announces-

Top-Line-Results-for-Cardiovascular-Outcomes-Study-of-Lyxumia-lixisenatide.

Neurotransmitter Dysfunction

HYPERGLYCEMIA

Decreased Incretin Effect Decreased Insulin

Secretion

Increased HGP

Islet–a cell

Increased Glucagon Secretion

Increased Lipolysis

Increased Glucose

Reabsorption

Decreased Glucose Uptake

DeFronzo, 2009.

Ominous Octet in Pathophysiology of T2DM: Need for Novel Therapies

Aretaeus of Capadocia & the First Description of Diabetes: Debut of the Kidneys!

Cereals once a day Goat milk at lunch

Concoction of dates, raw quinces, rose oil Advise to strengthen the stomach (the

fountain of thirst) Laios et.al. Hormones 2012, 11(1):

109-113

Felig et al, 1975. Wahren et al, 1975.

Gerich, 2010. Cersosimo et al, 2000.

*DeFronzo and Wahren, unpublished results.

Glucose Production Gluconeogenesis (20% of EGP) Kidney contains little glycogen

Glucose Utilization Net renal balance = zero

Glucose Reabsorption SGLT2 (80-90%) SGLT1 (10-20%)

Role of the Kidney in Blood Glucose-Level Regulation

Nair S, Wilding JPH. JCEM. 2010;95:34-42

Blood glucose is freely filtered by glomeruli and essentially completely reabsorbed from proximal renal tubules

When BG reaches ~10 mmol/L (180 mg/dL), glycosuria begins S1 and S2 segments show low affinity and high capacity for glucose

reabsorption in proximal tubules S3 segments have high affinity, low capacity In diabetes there is up-regulation of SGLT2 Thus, inhibition of SGLT2 in diabetes likely to produce greater glucosuria in

presence of hyperglycemia

Renal Glycosuria: Role in Health and Treatment Opportunity in Disease

Renal Threshold “Maladaptation” in Diabetes

Renal threshold for glucose reabsorption (TmG) is increased by 20-40% in type 2 diabetes (Farber SJ et al. J Clin Invest 1951; 30:125-29)

Similar elevations have been reported in type 1 diabetes (Morgensen CE. Scand J Clin Lab Invest 1971;28:101-09)

Cultured human renal tubular cells show enhanced SGLT-2 expression, its protein concentration with augmented glucose transport capacity (Rahmoune H et al. Diabetes. 2005;54:3427-34)

This represents a maladaptive response in diabetes aimed at conservation of glucose for energy needs

Upregulation of SGLT-2 Transporter and Enhanced Glucose Uptake in T2DM*

7 Transporter Protein Expression

Healthy Type 2 Diabetes

1 0

3 2

5 4

6

SGLT2 GLUT2

Nor

mal

ized

Glu

cose

Tr

ansp

orte

r Le

vels

P<0.05

P<0.05 Cellular Glucose Uptake

500

1000

1500

2000

2500

0

AMG

* U

ptak

e (C

PM)

P<0.05

38

Rahmoune H, et al. Diabetes. 2005;54:3427-3434.

*Primary Cultured Proximal Tubule Epithelial Cells

*AMG, methyl-α-D-[U-14C]-glucopyranoside

Healthy Type 2 Diabetes

*AMG, methyl-α-D-[U-14C]-glucopyranoside

SGLT 2

RENAL HANDLING OF GLUCOSE (180 L/day) (900 mg/L) = 162 g/day

10%

90%

NO GLUCOSE

S3 S1 S GL T 1

The Prospect of SGLT2 Inhibition

Plasma Glucose Conc (mg/dl)

300 200 100

Glu

cose

Rea

bsor

ptio

n an

d Ex

cret

ion

180

Splay

Actual Threshold

TmG

Theoretical threshold

Renal Glucose Handling

Plasma Glucose Conc (mg/dl)

TmG

Renal Glucose Handling in Diabetes

300 200 100

Glu

cose

Rea

bsor

ptio

n an

d Ex

cret

ion

180

Unique MOA of SGLT2 Inhibitors

Wright et al, 2007.

Abdul-Ghani, 2008.

Chao et al, 2010.

SGLT1

~180 g/day

10% Glucose

Normally no glucosuria

S1

S3

SGLT2

90%

Normally all filtered glucose is reabsorbed

SGLT-2 inhibitors Increase

renal glucose elimination

X

1. Santer R et al J Am Soc Nephrol2003;14(11); 2873-2882 2. CaladoJ et al Nephrol Dial Transplant 2008;23(12): 3874-3879

3. YuL et al Hum Genet 2011; 129 (3): 335-344 4. ChaoEC Nat Rev Drug Discov 2010; 9(7): 551-559

Familial renal glucosuria (FRG) is a rare inherited condition (partial or complete) in which SGLT2 lacks activity due to mutations in the SGLT2 gene1-4 The condition is defined by persistent urinary glucose excretion1,2,3

No hyperglycemia or diabetes is present1-4

No obvious clinical problems/renal defects or physiologic compensation despite defect in functional SGLT2 1,2

Proof of Premise that Lack of SGLT2 Activity is Compatible with Normal Function

T2DM + Dapagliflozin

40

Uri

nary

Glu

cose

G

luco

se E

xcre

tion

Plasma Glucose Conc (mg/dl)

260 180 100 220

0

50

100 Normal

(180 mg/dl) T2DM (220 mg/dl)

DeFronzo et al, 2013.

Effect of Dapagliflozin On Renal Threshold For Glucose in Diabetes

Actions of Known SGLT2 Inhibitors

Observed Effect(s) Reduced FPG + + + 0 + + + +

Reduced PPG + + + + + + + +

A1C Reduction

Gut CHO uptake

+

+

+

ND

+

ND

+

ND

+

ND

+

ND

+

ND

+

+

Weight loss + + + + + + + +

BP Reduction + + + + + + + +

Complementary MOA

+ + + + + + + +

Safety/Tolerability Durability ND= not determined Highlighted = FDA approved

+ +/-

+ +

+ ND

ND ND

ND ND

ND ND

ND ND

ND ND

Adapted from Rodbard HW, et al. Endocrine Pract. 2009;15:541-559.

*TZD contraindicated in class 3 or 4 CHF. †Unless used with TZD.

Glucosuria Excretion of excess glucose and

calories 46

Benefits of SGLT2 Inhibition

HbA1c lowering reduction in FPG & PPG

Reduction in weight

Reduction in blood pressure

Cardiovascular Safety of SGLT2 Inhibitors

• EMPA-REG-OUTCOME1

n=7034 T2DM patients Primary endpoint = time to first occurrence of either CV death

or non-fatal myocardial infarction or non-fatal stroke

Empagliflozin was superior to standard of care in CV risk reduction

1. Available at: www.boehringer-ingelheim.com/news/news_releases/press_releases/2015/20_august_2015_diabetes.html.

Agent – Trial Title Status of Long-term CV Safety Trials in Populations at Increased Risk for CV Events

Empagliflozin– EMPA-REG Superior to standard of care for CV risk reduction

Dapagliflozin– DECLARE Anticipated completion 2019

Canagliflozin - CANVAS Anticipated completion 2017

In addition to the advances made in oral treatment

approaches for T2DM, we are seeing the emergence of major

improvements in the capabilities of injectable and

other therapies as well!

Inhaled Dance-501 Human Insulina (in T2DM)

Randomized crossover trial of 24 patients with T2DM with normal lung function.

a Dance-501 is not currently approved by the US FDA. Zijlstra E, et al. Diabetes. 2015;64(suppl 1):A248 [abstract 978-P].

Dose levels: • LIS med: 18 U

• INH high: 207.7 IU, equivalent to SC: 27 IU • INH med: 138.5 IU 18 IU • INH low: 69.2 IU 9 IU

4

3

2

1

0

GIR

, mg/

kg/m

in

0 240 360 480 600 720 Time (min)

120

Time-Action Profile

LIS med INH high INH med INH low

• Inhaler device produces a fine mist of aerosolized liquid human

insulin for inhalation

• Coughing observed in 0.6% of inhalations

• No clinically relevant changes in measures of lung function at

postinhalation or during follow-up

Ultrarapid-Acting Insulin Lisproa (in T1DM)

Randomized, 4-period crossover study in 38 male patients with T1DM.

a BC lispro is not currently approved by the US FDA.

b 0.2 units/kg dose.

Andersen G, et al. Diabetes. 2015;64(suppl 1):A248 [abstract 979-P].

Difference in GIR Between

BC LIS and LIS

0

1

2

3

4

5

6

7

8

0 60 120 180 240 300 360 420 480

BC LIS 0.2 U/kg LIS 0.2 U/kg

Time, min

GIR

, mg/

kg/m

in

0 60 120 180 240 300 360 420 480

Time, min

0

2

4

6

8

10

12

GIR

, mg/

kg/m

in

BC LIS 0.2 U/kg BC LIS 0.1 U/kg

BC LIS 0.4 U/kg

BC LIS Linear Dose Response

• 48% earlier t1/2 max for BC lispro vs lispro (14 min vs 27 min, P < .0001)b

• 67% higher GIR for BC lispro in the first hour postinjection (P < .0001)b

• 18% lower GIR for BC lispro at 3-8 hours postinjection (P < .02)b

US FDA. Drugs@FDA. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA.

Basal insulins

Human insulins (intermediate

acting)

U-100 NPH

Analogues (long acting)

U-100 glargine

U-100 detemir

U-100 biosimilar glarginea

Analogues (ultralong acting)

U-300 glargine

U-100 degludecb

U-200 degludecb

Peglisproc

Blue boxes = FDA Approved a Tentatively approved by the FDA in August 2014; final approval is expected December 15, 2016. b Approved by the US FDA in September 2015. c Not currently approved by the US FDA.

Pharmacokinetic Profile of Basal Insulins

NPH = neutral protamine Hagedorn Adapted from Hirsh IB. NEJM. 2005; 352:174-183. Flood TM. J Fam Pract. 2007;56(suppl 1):S1-S12. Becker

RH, et al. Diabetes Care. 2014;pii:DC_140006.

0:00 12:00 16:00 20:00 24:00 8:00 4:00

Plas

ma

Insu

lin L

evel

s

2:00 14:00 18:00 22:00 10:00 6:00

Intermediate (NPH insulin) Long (Insulin detemir)

Long (Insulin glargine)

Time (h) 26:00 28:00 30:00 32:00 34:00 36:00

Ultra long (U300 glargine)

New Partnership Possibilities Based on Mechanisms of Action: Insulin Compared With GLP-1 Receptor Agonists

Class of Agent Mechanism(s) of Action Administration

Insulin1,2 Hepatic glucose production Glucose disposal Glucose uptake in muscle

Subcutaneous injection

GLP-1 Receptor Agonists1,3,4 Insulin secretion Hepatic glucose production Gastric emptying/glucose absorption Satiety

Subcutaneous injection

1. Inzucchi SE, et al. Diabetes Care. 2015;38:140-149;

2. Aronoff SL, et al. Diabetes Spectrum. 2004;17:183-190;

3. Drucker D, et al. Diabetes Care. 2010;33:428-433;

4. Rodbard H, et al. Endocr Pract. 2009;15:540-559.

Considerations for Advancing Therapy to Include GLP-1 Receptor Agonists or Insulin

GLP-1 Receptor Agonists

Advantages • Robust A1C change • Low hypoglycemia risk • Weight loss/avoidance of weight gain • Multiple dosing options with available

agents

Limitations • Training required for injection • GI adverse effects • Contraindicated/not recommended in

some populationsa

Insulin

Advantages • Theoretically unlimited efficacy • Universal effectiveness

Limitations • Training required for injection • SMBG (dose adjustment, hypoglycemia

avoidance) • Hypoglycemia • Weight gain

a Patients with MEN2 or with a personal or family history of MTC (ALBI, DULA, EXN QW, LIRA); patients with a history of pancreatitis (all); patients with severe RI/ESRD (EXN BID, EXN QW).

1. Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48; 2. Inzucchi SE, et al. Diabetes Care. 2015;38:140-149; 3.

US http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/; 4. Dulaglutide prescribing information. http://pi.lilly.com/us/trulicity-uspi.pdf.

Glycemic Efficacy of GLP-1 RAs Compared With Basal Insulin When Intensifying Oral Therapy: Incretin before Insulin?

Background Therapy Change in A1C, % GLP-1 RA

Change in A1C, % Basal Insulin

MET + SU1,a −1.1 Exenatide BIDe

−1.1 Glargine

MET + SU2,b −0.7 Albiglutidee

−0.8 Glargine

MET + GLIM3,a −1.3 Liraglutidef

−1.1 Glargine

MET ± SU4,a,c −1.3 Exenatide QWf

−0.9 Detemir

MET + GLIM5,d −1.1 Dulaglutidef

−0.6 Glargine

a 26 weeks, BL A1C 8.2% to 8.4%. b 52 weeks, BL A1C 8.3%, 82% on MET + SU background. c ≈ 70% on MET + SU background. d 52 weeks, BL A1C 8.1%. e Noninferior vs insulin. f P < .05 vs insulin.

1. Heine R, et al. Ann Intern Med. 2005;143:559-569; 2. Pratley R, et al. ADA 73rd Scientific Sessions. 2013 [abstract 54-LB];

3. Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055; 4. Davies M, et al. Diabetes Care. 2013;36:1368-1376;

5. Giorgino F, et al. Diabetes. 2014;63(suppl 1):A87.

Weight Effects With GLP-1 RAs Compared With Basal Insulin When Intensifying Oral Therapya

a P < .05 for between-group difference. 1. Heine R, et al. Ann Intern Med. 2005;143:559-569; 2. Pratley R, et al. ADA 73rd Scientific Sessions. 2013 [abstract 54-LB]; 3. Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055; 4. Davies M, et al. Diabetes Care. 2013;36:1368-1376; 5. Giorgino F, et al. Diabetes. 2014;63(suppl 1):A87; 6. Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48.

Agent GLP-1 Receptor Agonist Insulin

Impact on weight6 Loss Gain

1.8 1.56 1.6 0.8

1.44

−2.3

−1.05 −1.8

−2.7 −1.87 -3

-2-10123

MET + SU MET ± SU MET + GLIM MET ± SU MET + GLIM

Δ W

eigh

t, kg

Dulaglutide Exenatide BID Liraglutide

Exenatide QW Detemir

Glargine Albiglutide 1 2 3

4

5

Risk of Hypoglycemia With GLP-1 RAs Compared With Basal Insulin When Intensifying Oral Therapy

Hypoglycemia Type Comparison

Severe hypoglycemia

Liraglutide > Glargine1 (0.06 vs 0 events per year [EPY])

Dulaglutide ≈ Glargine2 “Minimal”

Nocturnal hypoglycemia Glargine > Exenatide BID3,4

Minor hypoglycemia Glargine > Exenatide QW5

Exenatide QW ≈ Detemir6

Overall hypoglycemia Glargine > Dulaglutide2

Glargine > Albiglutide7

1. Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055; 2. Giorgino F, et al. Diabetes. 2014;63(suppl 1):A87; 3. Heine R, et al. Ann Intern Med. 2005;143:559-569; 4. Davies M, et al. Diabetes Obes Metab. 2009;11:1153-1162; 5. Diamant M, et al. Lancet. 2010;375:2234-2243; 6. Davies M, et al. Diabetes Care. 2013;36:1368-1376; 7. Pratley R, et al. ADA 73rd Scientific Sessions. 2013 [abstract 54-LB]; 8. Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48.

Agent GLP-1 Receptor Agonist Insulin

Risk of hypoglcyemia8 Neutral Moderate to severe

Postprandial Glucose (PPG) Can Remain Uncontrolled With Basal Insulin Therapy

1. Monnier L, et al. Diabetes Metab. 2006;32:S11-S16; 2. Colclough HA, et al. Diabetes. 2012;63(suppl 1):A87.

Glucose Triad1

A1C

FPG PPG

• Patients with T2DM can experience significant PPG excursions, even with good control according to A1C and FPG measurements1

• 40% of patients treated with oral therapy and basal insulin had controlled FPG, but not A1C2

Baggio LL, Drucker DJ. Gastroenterology. 2007;132:2131-2157; Balena R, et al. Diabetes Obes Metab. 2013;15:485-502; Holst JJ. Physiol Rev. 2007;87:1409-1439.

Complementary Actions of Basal Insulin and GLP-1 RAs

β- and α-cell dysfunction Basal

insulin decreases hepatic

glucose production

by targeting the liver to decrease gluconeogenesis

and glycogenolysis

Main clinical effect: fasting BG control

Prandial GLP-1 RA improves β-cell

(insulin) and α-cell (glucagon)

function, delays gastric emptying

Main clinical effect: postprandial BG control

Optimal glycemic control (A1C)

Hepatic glucose overproduction

Not studied nor approved for use in

combination with basal insulin

• Dulaglutide • Exenatide QW

(prescribing information cautions against combination use)

Approved for use in combination with basal

insulin

• Albiglutide • Exenatide BID • Liraglutide

Approved for use with prandial insulin

• Dulaglutide

1. US FDA. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA; 2. Dulaglutide prescribing information. http://pi.lilly.com/us/trulicity-uspi.pdf; 3. Inzucchi SE, et al. Diabetes Care. 2015;38:140-149; 4. Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48.

Specific Guidance Regarding the Use of GLP-1 RAs in Combination With Insulin

Of the 5 currently available GLP-1 receptor agonists1-4:

The Emergence of New Targets and Tools for Treatment Approaches to Type 2 Diabetes Creates New Paradigms

• The urgency for early reduction of glucose toxicity is high! • Multiple possibilities have emerged as new treatment targets, like gut • Although appealing, the gut presents a complex target for glucose control • The mechanisms of glucose handling by kidney are now well-understood • The treatments that target the kidney are direct and glucocentric • Multiple benefits derive from glucose reduction through the kidney • There are now multiple possible partnerships for combination therapy! • Injectable therapy is undergoing a similar transformation! With improved safety! • Such developments now make it possible to actually TREAT diabetes in a more

physiologically comprehensive fashion---we are no longer limited to chasing BG!

Earlier and More Regular Use of Combination Therapy May Improve Treating to Target Compared with

Conventional Therapy

Del Prato S, et al. Int J Clin Pract. 2005;59(11):1345-1355. Campbell IW. Br J Cardiol. 2000;7:625-631.

Mean HbA1c

of patients

Time

Duration of Diabetes

10

6

8

9

7

OAD monotherapy

Diet and exercise

OAD combination

OAD uptitration OAD +

multiple daily insulin injections OAD +

basal insulin

Early Combination Approach H

bA1c

(%)