DIABETES UPDATE – NON INSULIN THERAPY FOCUS ON: INCRETIN THERAPY (DPP41, GLP1-RA) & SGLT2 INHIBITORS

American College of Physicians (ACP)

Northern California Chapter Scientific Meeting

Walnut Creek (2017)

Jaiwant Rangi, MD, FACE

Disclosures

Consultant and Speaker for Sanofi,

Boehringer- Ingelheim, Astra Zeneca, Dexcom,

AbbVie and Jannsen

Available Drugs for the Treatment

of Type 2 Diabetes Mellitus- 2017

Non-Insulin Agents Available for

Treatment of Type 2 Diabetes Class Primary Mechanism of Action Agent Available as

ALPHA GLUCOSIDASE

INHIBITORS

Delay carbohydrate absorption

from intestine

Acarbose Precose or generic

Miglitol Glyset

AMYLIN

ANALOGUES

Decrease glucagon secretion

Slow gastric emptying

Increase satiety

Pramlintide Symlin

BIGUANIDES

Decrease HGP

Increase glucose uptake in

muscle

Metformin Glucophage or generic

BILE ACID SEQUESTRANTS

Decrease absorption / HGP?

Increase incretin levels? Colesevelam WelChol

DPP-4 INHIBITORS

Increase glucose-dependent

insulin secretion

Decrease glucagon secretion

Alogliptin Nesina

Linagliptin Tradjenta

Saxagliptin Onglyza

Sitagliptin Januvia

DOPAMINE

AGONISTS

Activates dopaminergic

receptors Bromocriptine Cycloset

Non-Insulin Agents Available

for Treatment of Type 2

Diabetes Class Primary Mechanism of Action Agent Available as

GLINIDES Increase insulin secretion Nateglinide Starlix or generic

Repaglinide Prandin

GLP-1 RECEPTOR AGONISTS

Increase glucose-dependent

insulin secretion

Decrease glucagon secretion

Slow gastric emptying

Increase satiety

Exenatide Byetta

Exenatide XR Bydureon

Liraglutide Victoza

Albiglutide

Tanzeum

Dulaglutide Trulicity

Lixisenatide Lyxumia *

SGLT2 INHIBITORS Increase urinary excretion of

glucose

Dapagliflozin Farxiga

Canagliflozin Invokana

Empagliflozin Jardiance

Iprafliflozin Suglat

SULFONYLUREAS Increase insulin secretion

Glimepiride Amaryl or generic

Glipizide Glucotrol or generic

Glyburide Diaeta, Glynase, Micronase, or generic

THIAZOLIDINEDIONES (TZD’S)

Increase glucose uptake in

muscle and fat

Decrease HGP

Pioglitazone Actos

Rosiglitazone Avandia

Combination Agents Available for the Treatment of

Type 2 Diabetes

Class Added Agent Available as

DPP4i + SGLT2i Saxagliptin/Empagliflozin Glyxambi

METFORMIN + DPP-4 INHIBITOR Alogliptin Kazano

Linagliptin Jentadueto

Saxagliptin Kombiglyze XR

Sitagliptin Janumet

METFORMIN + GLINIDE Repaglinide Prandimet

METFORMIN + SGLT2 INHIBITORS Canagliflozin Invokamet Dapagliflozin Xigduo Empagliflozin Synjardy

METFORMIN + SULFONYLUREA Glipizide Metaglip and generic

Glyburide Glucovance and generic

METFORMIN + THIAZOLIDINEDIONE Pioglitazone Actoplus Met

Rosiglitazone Avandamet

TZD + DPP-4 INHIBITOR Pioglitazone + alogliptin Oseni

TZD + SULFONYLUREA Pioglitazone + glimepiride Duetact

Rosiglitazone + glimepiride Avandaryl

Updated Metformin – CKD Prescribing Guidelines (April 2016)

Obtain eGFR before starting metformin and annually, more frequently in

those at risk for renal impairment (e.g., elderly).

Metformin contraindicated in patients with an eGFR <30

Starting metformin in patients with an eGFR between 30-45 not

recommended

If eGFR falls <45, assess the benefits and risks of continuing

treatment. D/C if eGFR falls <30

Hold metformin at the time of / before iodinated contrast procedure if

eGFR 30-60; if H/o Liver disease, Alcoholism, or Heart failure; or if

Intra-arterial contrast. Recheck eGFR 48 hrs after procedure and restart

if renal function stable

http://www.fda.gov/Drugs/DrugSafety/ucm493244.htm (accessed 4-8-16)

Hyperglycemia

β α

Treatment based on pathophysiology

INSULIN

RESISTANCE

↑glucose reabsorption

↓insulin 50-80%

at diagnosis

↑Hepatic glucose

production

Decreased

incretin effect

and faster carb

absorption

Neurotransmitter

dysfunction

Decreased glucose

uptake

DeFranzo R, et al. Diabetes Care, Volume 36, Supplement 2, August 2013 S127-138

Islet- α cell

↑ glucagon

secretion

Lipolysis

increased

DPP IV inhibitors

GLP-1 agonists

Sulfonylureas

Meglitinides

Insulin GLP-1 agonists

SGLT-2

inhibitors

TZDs

Insulin Insulin

TZDs

GLP-agonists

DPP IV inhibitors

Metformin

Incretin Based Therapy

GLP-1 receptor agonists (injectable therapies) Exenatide

Liraglutide

Dulaglitide

Abiglutide

DPP-4 inhibitors (oral therapies) Sitagliptin

Saxagliptin

Linagliptin, Alogliptin

DPP – 4 Inhibitor's DIPEPTIDYL PEPTIDASE 4 INHIBITORS (GLIPTINS)

DPP-4 Inhibitors Alogliptin, Linagliptin, Saxagliptin, Sitagliptin

Mechanism Inhibit enzymatic degradation of GLP-1 and GIP; glucose-dependent

Efficacy Decrease A1C levels 0.6%–0.9%

Dosing Once daily

Side effects Headaches, nasopharyngitis

Main risk Viral infection; 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 polypeptide; GLP-1 = glucagon-like peptide-1

DPP-4 Inhibitors

FDA-Approved

Agents

Alogliptin

Linagliptin

Saxagliptin

Sitagliptin

Key Features

Oral administration

Increase endogenous GLP-1

and GIP levels

Increase glucose-dependent

insulin secretion

Suppress glucagon production

Monotherapy Add-on to Metformin Add-on to SU

Alo1 Lin2 Sax3 Sit4 Alo5 Lin6 Sax7 Sit8 Alo9 Lin10,* Sax11 Sit12,†

Baseline A1C (%) 7.9 8.0 8.0 7.5 8.1 8.2 8.6 8.4 7.8 7.9 8.5 8.3

Glucose Control with DPP-4 Inhibitors

-0.57 -0.5 -0.53

-0.69 -0.64 -0.62 -0.65

-0.83 -0.72

-0.67 -0.65 -0.74

-1

-0.8

-0.6

-0.4

-0.2

0

Placebo-Adjusted Change from Baseline

(Not Head-to-Head Trials)

*SU + metformin. †With or without metformin. ‡Absolute change from baseline (active-controlled trial).

1. DeFronzo RA, et al. Diabetes Care. 2008;31:2315–2317. 2. Del Prato S, et al. Diabetes Obes Metab. 2011;13:258-267.

3. Rosenstock J, et al. Curr Med Res Opin. 2009;25:2401-2411. 4. Nauck MA, et al. Diabetes Obes Metab. 2007;9:194-205. 5. Nauck MA, et al. Int

J Clin Pract. 2009;63:46-55. 6. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65-74. 7. DeFronzo RA, et al. Diabetes Care. 2009;32:1649-1655.

8. Charbonnel B, et al. Diabetes Care. 2006;29:2638-2643. 9. Pratley RE, et al. Diabetes Obes Metab. 2009;11:167-176. 10. Owens DR, et al.

Diabet Med. 2011;28:1352-61. 11. Chacra AR, et al. Int J Clin Pract. 2009;63:1395-1406. 12. Hermansen K, et al. Diabetes Obes Metab. 2007;9:733-745.

Pla

ce

bo

-ad

just

e

d

A1

C (

%)

‡

Monotherapy Add-on to Metformin Add-on to SU

Alo1 Lin2 Sax3 Sit4 Alo5 Lin6 Sax7 Sit8 Alo9 Lin10,* Sax11 Sit12,†

Weight Change with DPP-4 Inhibitors

-0.22 -0.3

0.68

-0.4

0.27

-0.1

-0.87

0.8

-1.5

0.8

-2

-1.5

-1

-0.5

0

0.5

1

Absolute Change from Baseline

(Not Head-to-Head Trials)

NR, value not reported.

*SU + metformin. †With or without metformin.

1. DeFronzo RA, et al. Diabetes Care. 2008;31:2315–2317. 2. Del Prato S, et al. Diabetes Obes Metab. 2011;13:258-267.

3. Rosenstock J, et al. Curr Med Res Opin. 2009;25:2401-2411. 4. Nauck MA, et al. Diabetes Obes Metab. 2007;9:194-205. 5. Nauck MA, et al. Int

J Clin Pract. 2009;63:46-55. 6. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65-74. 7. DeFronzo RA, et al. Diabetes Care. 2009;32:1649-1655.

8. Charbonnel B, et al. Diabetes Care. 2006;29:2638-2643. 9. Pratley RE, et al. Diabetes Obes Metab. 2009;11:167-176. 10. Owens DR, et al.

Diabet Med. 2011;28:1352-61. 11. Chacra AR, et al. Int J Clin Pract. 2009;63:1395-1406. 12. Hermansen K, et al. Diabetes Obes Metab.

2007;9:733-745.

W

eig

ht

(kg

)

NR NR

Monotherapy Add-on to Metformin Add-on to SU

Alo1 Lin2 Sax3 Sit4 Alo5 Lin6 Sax7 Sit8 Alo9 Lin10,* Sax11 Sit12,†

Hypoglycemia with DPP-4 Inhibitors

1.5 0

9.6

0.3 0.6

22.7

5.2 5.2

14.6

4.9

1.3

12.2

0

5

10

15

20

25

Percentage of Patients Reporting Hypoglycemia

(Not Head-to-Head Trials)

NR, value not reported.

*SU + metformin. †With or without metformin.

1. DeFronzo RA, et al. Diabetes Care. 2008;31:2315–2317. 2. Del Prato S, et al. Diabetes Obes Metab. 2011;13:258-267.

3. Rosenstock J, et al. Curr Med Res Opin. 2009;25:2401-2411. 4. Nauck MA, et al. Diabetes Obes Metab. 2007;9:194-205. 5. Nauck MA, et

al. Int J Clin Pract. 2009;63:46-55. 6. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65-74. 7. DeFronzo RA, et al. Diabetes Care.

2009;32:1649-1655. 8. Charbonnel B, et al. Diabetes Care. 2006;29:2638-2643. 9. Pratley RE, et al. Diabetes Obes Metab. 2009;11:167-176.

10. Owens DR, et al. Diabet Med. 2011;28:1352-61. 11. Chacra AR, et al. Int J Clin Pract. 2009;63:1395-1406. 12. Hermansen K, et al.

Diabetes Obes Metab. 2007;9:733-745.

Pa

tie

nts

(%

)

Incidence of Selected Adverse Events

with Sitagliptin: Pooled Data

Adverse Event Incidence per 100 patient-years Difference (95% CI)

Sitagliptin 100 mg Nonexposed

Constipation 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)

Nasopharyngitis 7.7 7.0 0.9 (-0.3, 2.1)

Pancreatitis 0.08 0.10 -0.02 (-0.20, 0.14)

Rash 1.3 0.9 0.4 (-0.1, 0.8)

Upper respiratory tract infection

8.6 9.0 -0.3 (-1.6, 1.0)

Williams-Herman D, et al. BMC Endocr Disord. 2010;10(7) . http://www.biomedcentral.com/1472-6823/10/7.

Engel SS, et al. Int J Clin Pract. 2010;64:984-990.

GLP-1's GLUCAGON LIKE PEPTIDE –1 INHIBITOR'S

GLP-1 Receptor Agonists

FDA-Approved Agents

Albiglutide

Dulaglutide

Exenatide

Exenatide ER

Liraglutide

Key Features

Injectable administration

Mimic action of native GLP-1

Increase glucose-dependent insulin

secretion

Suppress glucagon production

Slow gastric emptying

ER, extended release; GLP-1, glucagon-like peptide 1.

Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48.

Gastroenterology 2007 132, 2131-2157DOI: (10.1053/j.gastro.2007.03.054

Anti-diabetic Activities of GLP-1

Monotherapy Add-on to Metformin Add-on to SU

Alb1 Dul2 Exe3 Exe ER4

Lir5 Alb6 Dul7 Exe8 Exe ER9

Lir10 Alb11,* Exe12 Exe ER13,†

Lir14

Baseline A1C (%)

8.1 7.6 7.8 8.5 8.3 8.1 8.1 8.2 8.6 8.4 8.2 8.6 8.3 8.5

Glucose Control with

GLP-1 Receptor Agonists

-1.0 -0.9

-0.8 -0.8

-1.4

-1.0

-0.7 -0.9

-1.5 -1.5 -1.5 -1.4

-1.1

-1.5

-2

-1.5

-1

-0.5

0

Placebo-Adjusted Change from Baseline

(Not Head-to-Head Trials)

*Metformin with or without SU or TZD. †Metformin with or without SU. ‡Absolute change from baseline (active-controlled trial).

1. Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; 2014.

2. Umpierrez G, et al. Diabetes Care. 2014;37:2168-2176. 3. Moretto TJ, et al. Clin Ther. 2008;30:1448-1460. 4. Russell-Jones D, et al.

Diabetes Care. 2012;35:252-258. 5. Garber A, et al. Lancet. 2009;373:473-481. 6. Ahrén B, et al. Diabetes Care. 2014;37:2141-2148. 7.

Dungan KM, et al. Lancet. 2014;384:1349-1357. 8. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. 9. Bergenstal RM, et al. Lancet.

2010;376:431-439. 10. Pratley RE, et al. Lancet. 2010;375:1447-1456. 11. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289-297. 12.

Buse JB, et al. Diabetes Care. 2004;27:2628-2635. 13. Diamant M, et al. Lancet. 2010;375:2234-2243. 14. Marre M, et al. Diabet Med.

2009;26:268-278.

Pla

ce

bo

-ad

just

e

d

A1C

(%

)

‡

Monotherapy Add-on to Metformin Add-on to SU

Alb1 Dul2 Exe3 Exe ER4

Lir5 Alb6 Dul7 Exe8 Exe ER9

Lir10 Alb11,* Exe12 Exe ER13,†

Lir14

Weight Change with GLP-1

Receptor Agonists

-0.9 -1.2

-0.6

-2.3 -2.6

-1.6

-3.1 -2.8

-2.6

-2 -2.3

-0.2

-2.5

-3.4 -4

-3

-2

-1

0

*Metformin with or without SU or TZD. †Metformin with or without SU.

1. Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; 2014.

2. Umpierrez G, et al. Diabetes Care. 2014;37:2168-2176. 3. Moretto TJ, et al. Clin Ther. 2008;30:1448-1460. 4. Russell-Jones D, et al.

Diabetes Care. 2012;35:252-258. 5. Garber A, et al. Lancet. 2009;373:473-481. 6. Ahrén B, et al. Diabetes Care. 2014;37:2141-2148. 7.

Dungan KM, et al. Lancet. 2014;384:1349-1357. 8. DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. 9. Bergenstal RM, et al.

Lancet. 2010;376:431-439. 10. Pratley RE, et al. Lancet. 2010;375:1447-1456. 11. Pratley RE, et al. Lancet Diabetes Endocrinol.

2014;2:289-297. 12. Buse JB, et al. Diabetes Care. 2004;27:2628-2635. 13. Diamant M, et al. Lancet. 2010;375:2234-2243. 14. Marre M,

et al. Diabet Med. 2009;26:268-278.

W

eig

ht

(kg

)

Absolute Change from Baseline

(Not Head-to-Head Trials)

Blood Pressure Changes with Liraglutide

Monotherapy vs

Glimepiride

52 Weeks1

Add-on to

Metformin

26 Weeks2

Add-on to

Metformin

26 Weeks3

Add-on to

Sulfonylurea

26 Weeks4,5

Add-on to

Met + TZD

26 Weeks6

Add-on to

Met + SU

26 Weeks7

N 746 1091 665 1041 821 581

Treatment† Glim Lir Met Glim +

Met

Lir+ Met

Sit+ Met

Lir+ Met

SU Rosi + SU

Lir+ SU

Rosi + Met

Lir+ Rosi+ Met

Met+ SU

Glar+ Met+

SU

Lir+ Met+

SU

*P<0.05 vs comparator.

†All liraglutide 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.

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

-1.8 -2.3

-0.7

0.4

-0.9 -0.9 -1.1

0.5

-3.6

-2.3

-0.7

-2.8

-5.6

-4.0

-6

-5

-4

-3

-2

-1

0

1

S

ysto

lic B

P

(mm

Hg)

*

*

*

*

Monotherapy Add-on to Metformin Add-on to SU

Alb1 Dul2 Exe3 Exe ER4

Lir5 Alb6 Dul7 Exe8 Exe ER9

Lir10 Alb11,* Exe12 Exe ER13,†

Lir14

Hypoglycemia with GLP-1 Receptor Agonists

0 3

10.4 12.3

9

36

4.0 5.0

13.0

5.2 1

8.1 8

3

0

10

20

30

40

*Metformin with or without SU or TZD. †Metformin with or without SU.

1. Nauck M, et al. Diabetes. 2013;62(suppl 2): Abstr. 55-LB. 2. Umpierrez G, et al. Diabetes Care. 2014;37:2168-2176. 3. Moretto TJ,

et al. Clin Ther. 2008;30:1448-1460. 4. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258. 5. Garber A, et al. Lancet.

2009;373:473-481. 6. Ahrén B, et al. Diabetes Care. 2014;37:2141-2148. 7. Dungan KM, et al. Lancet. 2014;384:1349-1357. 8.

DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100. 9. Bergenstal RM, et al. Lancet. 2010;376:431-439. 10. Pratley RE, et al.

Lancet. 2010;375:1447-1456. 11. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2:289-297. 12. Buse JB, et al. Diabetes Care.

2004;27:2628-2635. 13. Diamant M, et al. Lancet. 2010;375:2234-2243. 14. Marre M, et al. Diabet Med. 2009;26:268-278.

Percentage of Patients Reporting Hypoglycemia

(Not Head-to-Head Trials) P

atie

nts

(%

)

Safety Considerations

with GLP1 Receptor Agonists

GI adverse

events

• Common • Usually dose dependent and transient • Usually reduced with dose titration

Pancreatitis

• Pancreatitis has been reported with postmarketing use of some of incretin agents, although no causal relationship has been established

• Extensive review by FDA of studies involving >80,000 patients has not uncovered reliable evidence of increased pancreatic risk with incretins vs other agents

• Labeling for all incretins states these agents should be immediately discontinued if pancreatitis is suspected

• Labeling for GLP-1 receptor agonists suggests consideration of other therapies for patients with a history of pancreatitis

Pancreatic

cancer

• Extensive review by FDA of studies involving >80,000 patients has not uncovered reliable evidence of increased pancreatic risk with incretins vs other agents

• Further assessments required from long duration-controlled studies or epidemiological databases

Medullary

thyroid

cancer

• Animal data showed an increased incidence of C-cell tumors with liraglutide and exenatide ER treatment, but confirmatory population studies are lacking

• Labeling for liraglutide and exenatide ER: • Patients should be counseled regarding medullary thyroid carcinoma and the signs/symptoms

of thyroid tumors • Contraindicated in patients with personal/family history of MTC or multiple endocrine neoplasia

syndrome type 2

Renal

impairment

• Renal Impairment has been reported postmarketing, usually in association with nausea, vomiting,

diarrhea, or dehydration. Use caution when initiating or escalating doses in patients with renal

impairment. Exenatide is contraindicated in patients with severe renal insufficiency or ESRD

ER, extended release.

Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48.

ADA/EASD/IDF statement concerning the use of incretin therapy and pancreatic disease [news release]. Alexandria, VA: American

Diabetes Association, European Association for the Study of Diabetes, International Diabetes Federation; June 28, 2013.

http://www.diabetes.org/newsroom/press-releases/2013/recommendations-for.html.

SGLT-2 Inhibitors SODIUM GLUCOSE CO-TRANSPORTER 2 INHIBITOR'S

SGLT2 Inhibitors Canagliflozin, Dapagliflozin, Empagliflozin

Invokana [Package Insert] Janssen Pharmaceuticals, Inc. Titusville, NJ.; Lavalle-gonzález FJ, Januszewicz A, Davidson J, et al.

Diabetologia. 2013; Stenlöf K, Cefalu WT, Kim KA, et al. Diabetes Obes Metab. 2013;15(4):372-82; Burki TK. Lancet. 2012;379(9815):507.

Mechanism Inhibits sodium-glucose transport protein subtype 2 (SGLT2) which is responsible for at least 90% of glucose reabsorption in the kidney causing blood glucose is eliminated in the urine

Efficacy Modest (HbA1C 0.8-1.1%)

Advantages

Insulin-independent glucose reduction, Low risk of hypoglycemia,

Weight loss (to 4% BW), Blood pressure-lowering

Disadvantages

Osmotic diuresis causing Polyuria and lightheadedness, Bacterial

urinary tract infections (≈5%), Fungal genital infections (≈10%),

Increased LDL cholesterol, Hyperkalemia (canagliflozin), Bladder

cancer concerns (dapagliflozin)

Contraindications History of genital fungal infections, caution in chronic kidney

disease

SGLT2 Inhibitors Promote Urinary Glucose

Excretion

SGLT2 mediates most (≈ 90%) glucose reabsorption from the proximal renal tubular lumen back into the circulation

SGLT2 inhibitors lower the

threshold at which glucose is excreted, leading to Increased urinary glucose

excretion Decreased return of

glucose to circulation Decreased blood glucose

levels

Bowman’s

capsule

Return

to

circulation

Urinary excretion

Glucose

SGLT2

Proximal

renal

tubule

Sodium-glucose co-transporter 2 inhibitors

(SGLT2)

Benefits:

Weight loss

Improved systolic BP

A1c reduction

Other effects

Increase LDL

Increase risk of yeast infections

Not recommended in over 75 y/o

Canagliflozin (Invokana 100 & 300 mg)

GFR>45 mL/min/1.73m²

Dapaglifozin (Farxiga 5 & 10 mg QD)

GFR>60

Empagliflozin (Jardiance 10 & 25 mg)

GFR>45

Glucose Control with SGLT2 Inhibitors

Placebo-Adjusted Change from Baseline

(Not Head-to-Head Trials)

*Absolute change from baseline (active-controlled trial).

1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-382. 2. Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224. 3. Roden M, et al.

Lancet Diabetes Endocrinol. 2013;1:208-219. 4. Cefalu WT, et al. Lancet. 2013;382:941-950. 5. Nauck MA, et al. Diabetes Care.

2011;34:2015-2022. 6. Haring HU, et al. Diabetes Care. 2014;37:1650-1659. 7. Yale J-F, et al. Diabetes Obes Metab. 2013;15:463-473. 8.

Wilding JPH, et al. Ann Intern Med. 2012;156:405-415. 9. Rosenstock J, et al. Diabetes Care. 2014;37:1815-1823.

Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs

Can1 Dap2 Emp3 Can4 Dap5 Emp6 Can7 Dap8 Emp9

Baseline A1C

(%)

8.1 7.8 7.9 8.1 8.2 7.9 8.2 8.6 8.3

Pla

ce

bo

-ad

just

ed

A1

C (

%)

*

*

-1.2

-0.9

-0.4

-0.66 -0.52 -0.57

-0.86

-0.64

-0.46

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

Weight Change with SGLT2 Inhibitors

Absolute Change from Baseline

(Not Head-to-Head Trials)

Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs

Can1 Dap2 Emp3 Can4 Dap5 Emp6 Can7 Dap8 Emp9

-3.4

-4.0

-1.4

-3.2 -3.2

-1.6

-2.48 -2.46 -2.04

-4.5

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-382. 2. Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224. 3. Roden M, et al.

Lancet Diabetes Endocrinol. 2013;1:208-219. 4. Cefalu WT, et al. Lancet. 2013;382:941-950. 5. Nauck MA, et al. Diabetes Care.

2011;34:2015-2022. 6. Haring HU, et al. Diabetes Care. 2014;37:1650-1659. 7. Yale J-F, et al. Diabetes Obes Metab. 2013;15:463-473. 8.

Wilding JPH, et al. Ann Intern Med. 2012;156:405-415. 9. Rosenstock J, et al. Diabetes Care. 2014;37:1815-1823.

W

eig

ht

(kg

)

Overseas phase III clinical study - A metformin combination study (D1690C00012)

Changes in body composition from the baseline (24 and 102 weeks after start of treatment)

Bolinder J. et al.: Diabetes Obes Metab. 16(2): 159-169, 2014

-5.0

-4.5

-4.0

-3.5

-2.0

-1.5

-0.5

Ch

an

ge

(24 Weeks)

Placebo + MET

(n=86)

Farxiga 10 mg + MET

(n=83)

(102 Weeks)

Placebo + MET

(n=71)

Total lean tissue mass

Total fat mass

0.0

-1.0

-2.5

-3.0

Farxiga 10 mg + MET

(n=66)

-0.65

-0.40

-2.16

-1.00

-1.46

-0.90 -2.80

-1.30

(kg)

Subjects: Patients with type 2 diabetes mellitus poorly controlled as to blood glucose by uncombined metformin (MET) therapy [182 patients included in safety analysis; 180 patients included in efficacy analysis (FAS)]

Methods: A randomized, double-blind, placebo-controlled, multicenter, parallel-group comparative study. Subjects were allocated at random to the Forxiga 10 mg + MET group and the placebo + MET group. Once daily treatment (combined with MET 1,500 mg/day) in the morning was continued for 102 weeks, and mean adjusted change in body composition at 24 and 102 weeks after the start of treatment was analyzed.

Safety: The incidence of adverse reactions was 19.8% (18/91) in the Forxiga 10 mg + MET group and 14.3% (13/91) in the placebo + MET group.

Adjusted mean change (95% CI)

FAS

(including data after hyperglycemia rescue therapy) MET: Metformin

Note) The starting dose level of Forxiga Tablet in Japan is 5 mg/day. Before use, reference to the latest package insert is needed.

Blood Pressure Changes with SGLT2 Inhibitors

Absolute Change from Baseline (Not Head-to-Head Trials)

1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-382. 2. Ferrannini E, et al. Diabetes Care.

2010;33:2217-2224. 3. Roden M, et al. Lancet Diabetes Endocrinol. 2013;1:208-219. 4. Cefalu WT, et al.

Lancet. 2013;382:941-950. 5. Nauck MA, et al. Diabetes Care. 2011;34:2015-2022. 6. Haring HU, et al.

Diabetes Care. 2014;37:1650-1659. 7. Yale J-F, et al. Diabetes Obes Metab. 2013;15:463-473. 8. Wilding JPH, et al. Ann Intern Med. 2012;156:405-415. 9. Rosenstock J, et al. Diabetes Care. 2014;37:1815-1823.

Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs

Can1 Dap2 Emp3 Can4 Dap5 Emp6 Can7 Dap8 Emp9

-5.0 -4.6

-6.4

-3.6 -4.3

-6.7

-5.0 -5.2

-3.8

-8

-7

-6

-5

-4

-3

-2

-1

0

S

yst

olic

BP

(m

mH

g)

Hypoglycemia with SGLT2 Inhibitors

Percentage of Patients Reporting Hypoglycemia

(Not Head-to-Head Trials)

1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-382. 2. Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224. 3. Roden M, et al.

Lancet Diabetes Endocrinol. 2013;1:208-219. 4. Cefalu WT, et al. Lancet. 2013;382:941-950. 5. Nauck MA, et al. Diabetes Care.

2011;34:2015-2022. 6. Haring HU, et al. Diabetes Care. 2014;37:1650-1659. 7. Yale J-F, et al. Diabetes Obes Metab. 2013;15:463-473. 8.

Wilding JPH, et al. Ann Intern Med. 2012;156:405-415. 9. Rosenstock J, et al. Diabetes Care. 2014;37:1815-1823.

Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs

Can1 Dap2 Emp3 Can4 Dap5 Emp6 Can7 Dap8 Emp9

3.0 5.0

51.2

2.9 3.4

53.6

1.4

58.2

0

10

20

30

40

50

60

70

Pa

tie

nts

(%

)

<1

Safety Considerations with SGLT2 Inhibitors

Genitourinary infection

Increased incidence; patients should be monitored and treated if necessary

Increased LDL-C Small increases in LDL-C have been observed in clinical trials

Bladder cancer

Increased incidence of bladder cancers in patients receiving dapagliflozin

Dapagliflozin labeling recommends not using in patients with active bladder cancer and should be used with caution in patients with a history of bladder cancer

Renal impairment Monitor kidney function during therapy, especially in patients with GFR <60 mL/min/1.73 m2

Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48.

Farxiga (dapagliflozin) prescribing information. Princeton, NJ: Bristol-Meyers Squibb Company. 2014.

Invokana (canagliflozin) prescribing information. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2014.

Time course of eGFR (meta-analysis)

Changes in eGFR

4 8 16 24 37 50 1 63 76 89 102 (Week) BL

Number of patients

Placebo (n=1,955) C

ha

ng

e fro

m b

ase

lin

e in

eG

FR

(mL/min/1.73 m2)

2,026

1,955

1,697

1,629

1,655

1,570

1,777

1,671

1,600

1,513

1,663

1,558

Forxiga 10 mg

Placebo

712

605

692

585

656

551

627

521

10

15

5

0

-5

-10

-15

Farxiga 10 mg (n=2,026)

Baseline

Mean (mL/min/1.73 m2)

Placebo

Forxiga 10 mg 81.0

80.7

EMDAC data <http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm

378079.pdf>

Note) The starting dose level of Forxiga Tablet in Japan is 5 mg/day. Before use, reference to the latest package insert is needed.

Subjects/Methods: Meta-analysis of the combined subjects of Phase IIb/III studies conducted across the world (including Japan and Asia) (30-MU:

data cut off on November 15, 2012)

Prescribing Information Comparison* CANAGLIFLOZIN DAPAGLIFLOZIN EMPAGLIFLOZIN

Dosing • 100 mg once daily

before first meal

• 300 mg if eGFR ≥60 mL/min/1.73m2

• 5 or 10 mg once daily in morning, with

or without food

• 10 or 25 mg once daily in morning,

with or without food

Contraindications Severe renal impairment, ESRD, dialysis

• Do not initiate if eGFR

<45 mL/min/1.73m2

Severe renal impairment, ESRD, dialysis

• Do not initiate if eGFR

<60 mL/min/1.73m2

Severe renal impairment, ESRD, dialysis

• Do not initiate if eGFR

<45 mL/min/1.73m2

Warnings and

Precautions

• Hypotension

• Impaired renal function

• Hyperkalemia

• Hypoglycemia: concomitant insulin or

secretagogues

• Genital mycotic infections

• Hypersensitivity reactions

• LDL-C increases

• Hypotension

• Impaired renal function

• Hypoglycemia: concomitant insulin or

secretagogues

• Genital mycotic infections

• Bladder cancer imbalance

• LDL-C increases

• Hypotension

• Impaired renal function

• Hypoglycemia: concomitant insulin or

secretagogues

• Genital mycotic infections

• Urinary tract infections

• LDL-C increases

Key Adverse Events

(>5% incidence)

• Female genital mycotic infections

• Urinary tract infections

• Increased urination

• Female genital mycotic infections

• Nasopharyngitis

• Urinary tract infections

• Female genital mycotic infections

• Urinary tract infections

Differences are bold and in red.

*Accurate comparison of SGLT2 inhibitors requires head-to-head studies, which have not yet been conducted.

Farxiga (dapagliflozin) prescribing information. Princeton, NJ: Bristol-Meyers Squibb Company. 2014.

Invokana (canagliflozin) prescribing information. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2014.

Combination options (Basal Insulin and GLP-1 Agonists) for

the treatment of Type 2 diabetes

Xultophy (Degludec / Liraglutide)

Administered once daily by sc injection,

It is supplied as a 3ml prefilled pen containing 100 units/3.6mg insulin Degludec/liraglutide per ml;

The proportion of patients reaching target HbA1c was higher with Xultophy than with insulin degludec or

liraglutide

Adverse effects are typical of the component drugs, with a lower incidence of gastrointestinal effects but

less weight loss than Liraglutide

Soliqua (Glargine U-100 and Lixisenetide) LixiLan, single-injection fixed-ratio combination of GLP1-RA & Analog Basal Insulin- Lixisenatide (Lyxumia) &

Glargine (Lantus)

24-week, double-blind trial, 495 patients with type 2 diabetes inadequately controlled with Insulin Glargine

and Metformin (mean HbA1C 8.4 percent) were randomly assigned to the addition of Lixisenatide or

placebo

The reduction in A1C was significantly greater in the Lixisenatide group (-0.6 versus -0.3 percent)

CVOT's CARDIOVASCULAR OUTCOME TRIALS

Study SAVOR EXAMINE TECOS CAROLINA CARMELIN

A

DPP4-i saxaglip

tin

alogliptin sitaglipti

n

linagliptin linagliptin

Comparat

or

placebo placebo placebo sulfonylurea placebo

N 16,500 5,400 14,000 6,000 8,300

Results 2013 2013 June

2015

2017 2017 Study LEADER ELIXA SUSTAIN 6 EXSCEL REWIN

D

FREEDOM

GLP1-

RA

liraglutide lixisenatid

e

semaglutide exenatide

LR

Dulaglutide ITCA-

650

Comparat

or

placebo placebo placebo placebo Placebo

Placebo

N 16,500 14,000 6,000 5,400 8,300 4000+

Results 2016 2015 2016 2018 2019 2015

Study EMPA-REG CANVAS DECLARE NCT01986881

SGLT-2-i empaglifozin canagliflozin dapagliflozin ertugliflozin

Comparat

or

placebo placebo placebo placebo

N 7300 4300 22,200 3900

Results Sept 2015 2017 2019 2020

Large Non-Insulin CVOTs in T2DM

✓ ✓

✓

✓

POSITIVE

PROactive Study

>5,000 patients in 19 European countries involving over 320 investigators

Investigated effect of insulin resistance on CV morbidity and mortality in patients

with T2DM

Investigated Pioglitazone’s ability to prevent the progression of macrovascular

disease

PROspective Actos Clinical Trial In macroVascular Events (PROactive) results. http://www.proactive-results.com/html/about_the_study.htm Accessed February 2011.

CV = cardiovascular; T2DM = type 2 diabetes mellitus

All-cause mortality

Stroke

Leg revascularization

Non-fatal MI (including silent)

Major leg amputation

(above the ankle)

Acute coronary syndrome

Cardiac intervention

The primary endpoint was time to first occurrence of any of the following

events from time of randomization:

Dormandy JA, et al. Lancet. 2005;366:1279-1285.

Time to Fatal/Nonfatal MI

(excluding silent MI)

PROactive results Web site. Available at

http://www.proactive results.com

/html/analysis.htm. October 10, 2006.

Placebo

PIO

Ka

pla

n-M

eie

r Ev

en

t R

ate

(35/1230)

(54/1215)

HR 95% CI

P value

PIO vs placebo 0.63 0.41, 0.97 .035 2445 2397 2351 2308 2265 2222 406(139) N at

Risk: l 0

l 6

l 12

l 18

l 24

l 30

l 36

Time From Randomization (mo)

.0–

.01–

.03–

.04–

.05–

.06–

.02–

CV=cardiovascular; ACS=acute coronary syndromes; MI=myocardial infarction

The official PROspective Actos Clinical Trial In macroVascular Events

(PROactive) results website. Available at http://www.proactive-

results.com/html/analysis.htm.

Time to ACS

Time From Randomization (mo)

Ka

pla

n-M

eie

r Ev

en

t R

ate

.02–

.04–

.06–

.08–

.10–

.0–

0 6

12 18 24 30 36

2445 2387 2337 2293 2245 2199 399(139) N at

Risk:

HR 95% CI P value

0.72 0.52, 0.99 .045

Placebo

PIO (65/1230)

(88/1215)

PIO vs placebo

l

l

l

l

l

l

l

l

l

PROactive Study, Secondary Endpoints Pioglitazone Had No Significant Effect on Primary Composite CV Endpoints

Benefit Seen in Select Secondary Endpoints

Pioglitazone after Ischemic Stroke or Transient Ischemic Attack Primary Outcome

Kernan WN et al. N Engl J Med 2016;374:1321-1331

Pioglitazone after Ischemic Stroke or TIA Primary and Secondary Outcomes

Kernan WN et al. N Engl J Med 2016;374:1321-1331

EMPA-REG Clinical Outcomes with Empagliflozin

EMPA-REG OUTCOME Pooled Analysis

(N=7020)

*CV death, nonfatal MI (excluding silent MI), or nonfatal stroke; †CV death, nonfatal MI (excluding silent MI), nonfatal stroke, and hospitalization for unstable

angina.

CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction.

Zinman B, et al. N Engl J Med. 2015;373:2117-2128.

0.00 0.50 1.00 1.50

Hazard ratio (95%

CI) P value

Primary composite endpoint* 0.86 (0.74-0.99) 0.04

Secondary composite endpoint† 0.89 (0.78-1.01) 0.08

Death from any cause 0.68 (0.57-0.82) <0.001

CV death 0.62 (0.49-0.77) <0.001

Fatal or nonfatal MI 0.87 (0.70-1.09) 0.23

Hospitalization for HF 0.65 (0.50-0.85) 0.002

Hospitalization for HF or CV death 0.66 (0.55-0.79) <0.001

Favors empagliflozin

14%

36%

34%

32%

35%

CVOT- Empa-Reg Trial

Cum

ula

tive in

cid

ence fu

nctio

n. H

R, h

azard

ratio

HR 0.62 (95% CI 0.49, 0.77)

p<0.0001

Number needed to treat (NNT) to prevent one death

across landmark trials in patients with high CV risk

1. 4

S in

vestig

ato

r. Lancet 1

994; 3

44: 1

383

-89,

http

://ww

w.tria

lresults

cente

r.org

/stu

dy2590

-4S

.htm

;

2. H

OP

E in

vestig

ato

r N E

ngl J

Med 2

000;3

42:1

45

-53,

http

://ww

w.tria

lresults

cente

r.org

/stu

dy2606

-HO

PE

.htm

Simvastatin1

for 5.4 years

High CV risk 5% diabetes, 26% hypertension

1994 2000 2015

Pre-statin era

High CV risk 38% diabetes, 46% hypertension

Ramipril2

for 5 years

Pre-ACEi/ARB era

<29% statin

Empagliflozin for 3 years

T2DM with high CV risk 92% hypertension

>80% ACEi/ARB

>75% statin

LEADER (Liraglutide)- Primary outcome CV death, non-fatal myocardial infarction, or non-fatal stroke

The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke. The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; CV: cardiovascular; HR: hazard ratio.

Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

LEADER Trial Primary and secondary CV Outcomes

*Hazard ratios and p-values were estimated with the use of a Cox proportional-hazards model with treatment as a covariate. †The primary composite outcome in the time-to-event analysis consisted of the first occurrence of death from cardiovascular causes (181 patients in the liraglutide group vs. 227 in the placebo

group), non-fatal (including silent) myocardial infarction (275 vs. 304), or non-fatal stroke (152 vs. 163). The p-value is for superiority. ‡The expanded composite outcome included death from

cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or hospitalization for unstable angina pectoris or heart failure.

§This analysis was not prespecified. CI: confidence interval; CV: cardiovascular; UAP: unstable angina pectoris.

Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

LEADER Trial: Time to first renal event Macroalbuminuria, doubling of serum creatinine, ESRD, renal death

The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; ESRD: end-stage renal disease; HR: hazard ratio.

Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

LEADER TRIAL: NNT to treat to prevent one…

CV: cardiovascular; MACE: major adverse cardiovascular event.

Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

CANVAS: Canagliflozin and Cardiovascular and

Renal Events in Type 2 Diabetes

Compared with patients taking placebo, patients taking Canagliflozin had lower

A1C levels (mean difference -0.58 percent) and reductions in weight and systolic and diastolic blood pressure

After a mean follow-up of 3.6 years, the primary outcome, a composite of death

from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke,

occurred in fewer patients in the Canagliflozin group (26.9 vs. 31.5 patients per 1000

patient-years,

The rate of hospitalization for heart failure was lower in the canagliflozin group (5.5

versus 8.7 patients per 1000 patient-years in the placebo group, HR 0.67, 95% CI 0.52-

0.87)

Progression of albuminuria (a secondary endpoint) occurred less frequently in the Canagliflozin group (89.4 versus 128.7 participants per 1000 patient-years in the

placebo group, HR 0.73, 95% CI 0.67-0.79)

CANVAS and CANVAS -R

Adverse reactions were consistent with the previously reported risks associated

with canagliflozin except for an increased risk of amputation

Amputation incidence 5.9 and 2.8 per 1000 patient-years for patients taking

canagliflozin and placebo, respectively, in the first trial, and 7.5 and 4.2 per

1000 patient-years, respectively, in the second trial

Patients were followed for a mean 5.7 and 2.1 years, respectively

Amputations were primarily at the level of the toe or metatarsal

Patients with a history of prior amputation, peripheral vascular disease, and

neuropathy were at highest risk for amputation

Summary: CVOT's of SGLT-2 Inhibitors

The large cardiovascular benefit of Empagliflozin and Canagliflozin while

impressive, was in a very high-risk population with established CVD at baseline

Benefit in patients taking Canagliflozin must be balanced with the increased risk of

amputations

The difference in glycemia between the treatment groups was minimal,

suggesting that extra-glycemic effects of the drugs were responsible for the CVD

outcome

It is unknown whether Empagliflozin, Canagliflozin, or other SGLT2 inhibitors, will have similar CVD effects in the majority of persons with type 2 diabetes who do

not have overt CVD

Wait for DECLARE (with Dapagliflozin)

Look beyond your patient's HbA1c DIABETES TECHNOLOGY: CGMS, INSULIN PUMPS AND OTHER OPTIONS

Look Beyond Your Patient's HbA1c

Summary: DM Contemporary Care

Identify individual treatment goals

Institute personalized comprehensive care for people with diabetes

Start intensive lifestyle modification for glycemic control while concomitantly starting

medications

Choose medications based on safety, efficacy and characteristics

Monitor every three months intensify/advance treatment as needed

Per the AACE Algorithm Consider GLP1 RA and SGLT- 2 Inhibitors as first options with

metformin based on safety efficacy in reducing glucose and positive effect on CV

risk parameters especially weight and blood pressure

THANK YOU