AACE Diabetes Algorithm- Focus on: SGLT2-inhibitors and ...syllabus.aace.com/2018/PCP/ShermanOaks... · Yehuda Handelsman, MD, FACP, FNLA, MACE Courtyard by Marriott, Saturday, April

Yehuda Handelsman, MD, FACP, FNLA, MACECourtyard by Marriott, Saturday, April 7, 2018, Sherman Oaks, CA

AACE Diabetes Algorithm- Focus on:

SGLT2-inhibitors and GLP1-ra Therapies

California Chapter of the American Association of Clinical Endocrinologists

Presents:

Hot Topics in Diabetes and Endocrinology for Primary Care

Yehuda Handelsman, MD, FACP, FNLA, MACE

Medical Director & Principal investigator

Metabolic Institute of America

Chair

AACE/ACE Diabetes & lipid Scientific Committees

President

Pacific Lipids association

Program Chair & Director

“Heart in Diabetes” 7/13-15/2018, Philadelphia, PN16th WCIRDC 11/29-12/1/2018, Los Angeles, CA

Solo practice

Endocrinology, Diabetes & Metabolism

Tarzana, California

Handelsman Disclosures Research grant- Amgen, AZ, BMS, BI, Gan & Lee, Grifolis, Hamni,

Lexicon, Merck, Mylan, Novo Nordisk, Sanofi

Consultant – Aegerion, Amarin, Amgen, BMS, BI, Gilead, Janssen,

Lilly, Merck, Novo-Nordisk, Sanofi.

Speaker’s Bureau- Aegerion, Amarin, Amgen, AZ, BI-Lilly, Janssen,

Merck, Novo-Nordisk, Regeneron, Sanofi.

Dr Handelsman & his immediate family do not have ownership interest & or stocks of any Pharmaceutical or device company

Case : Jack, 63 years, male

Diagnoses:

• Diabetes mellitus Type 2 for 5 years

• Obesity BMI 31.3 kg/m²

• HTN

• Hyperlipidemia

• ASCVD- TIA (CVA?) 3 years ago; ACS 6 months ago.

Presentation to office for better lipid control

Physical exam:

• Height 176 cm

• Weight 97 kg BMI 31.3

• Waist circumference 101 cm,

• Blood pressure 145/88 mmHg

• Pulse 84 min.

• Pedal pulses palpable

• Pretibial edema bilaterally


The reason of the visit:

Consult to prevention of further ASCVD

Current medications:

• Metformin 1000 mg QD

• Aspirin 81 mg QD

• Prasugrel 10 mg QD

• Ramipril 5 mg QD

• Bisoprolol 5 mg QD

• Simvastatin 20 mg QD


Lab tests:• HbA1c 8.6%• Fasting glucose 137 mg/dl • Creatinine 1.4 mg/dl; GFR 56 ml/min)• BUN 28 mg/dl • Uric acid 7.8 mg/dl • GGT 91 U/l, AST 71 U/l, ALT 55 U/l

Lipid profile (on 20 mg Simvastatin):• Total cholesterol 218 mg/dl • Triglycerides 233 mg/dl • LDL-cholesterol 138 mg/dl • HDL-cholesterol 34 mg/dl • Lipoprotein(a) 36 mg/dl


Cardiovascular Risk Increases With

Diabetes and CKD

*ASVD was defined as the first occurrence of AMI, CVA/TIA, or PVD.

AMI, acute myocardial infarction; ASVD, atherosclerotic vascular disease.

CHF, congestive heart failure; CKD, chronic kidney disease; CVA/TIA, cerebrovascular accident/transient

ischemic attack; PVD, peripheral vascular disease;.

Foley RN, et al. J Am Soc Nephrol. 2005;16:489-495.

x 2.8

x 2.3

x 1.7

x 2.1

x 2.0

x 2.5

8

Type 2 Diabetesis a

Cardiovascular Disease

Treat All Risk Factors

Handelsman Y, 1998

A: Total deaths during 13.3 years (primary endpoint)B: Death from cardiovascular disease, nonfatal stroke, nonfatal myocardial

infarction, CABG, PCI, revascularization for atherosclerotic obstructive disease, outbreak of cardiovascular events including leg amputation (secondary combined endpoint)

C: Number of each event constituting the combined endpoint (bar for A and B indicates SE)

*Outbreak of cardiovascular events, etc. was compared between the standard therapy group (conventional multi-factor treatment applied) and the intensive therapy group (treatment applied with goal set at HbA1c < 6.5%, fasting total cholesterol < 175mg/dL, fasting triglycerides < 150mg/dL, systolic blood pressure < 130 mmHg and diastolic blood pressure < 80 mmHg).

10

Intensive Intervention in T2DM Reduced CV

Death and Improved Vascular Complications

Gaede P. et al.: N Engl J Med. 358(6): 580-591, 2008

Intensive therapy group Standard therapy group

Nu

mb

er

of

card

iov

ascu

lar

ev

en

ts

40

35

30

25

20

15

10

5

0Cardiovascular

death

Stroke Myocardial

infarctionCABG PCI Revasculariz

ation

Leg

amputation

C

Cu

mu

lati

ve d

eath

Total follow-up period0 1 2 3 4 5 6 7 8 9 10 11 12 13

Intensive therapy group

Standard therapy group

80

70

60

50

40

30

20

10

0

p=0.02

Number of surviving patients followed

80 78 75 72 65 62 57 39

80 80 77 69 63 51 43 30



(%)

(year)

A

Cu

mu

lati

ve

card

iov

ascu

lar

ev

en

ts

80

70

60

50

40

30

20

10

0

p<0.001



Total follow-up period0 1 2 3 4 5 6 7 8 9 10 11 12 13

Number of event-free patients

80 72 65 61 56 50 47 31

80 70 60 46 38 29 25 14



(%)

(year)

B

Total death and outbreak of cardiovascular events

(standard therapy vs intensive therapy)*

ENDOCRINE PRACTICE Vol 21 No. 4 April 2015

American Association of Clinical Endocrinologists andAmerican College of

Endocrinology Clinical Practice Guidelines for Developing a

Diabetes Mellitus Comprehensive Care Plan

Writing Committee Cochairpersons

Yehuda Handelsman MD, FACP, FACE, FNLA

Zachary T. Bloomgarden, MD, MACE

George Grunberger, MD, FACP, FACE

Guillermo Umpierrez, MD, FACP, FACE

Robert S. Zimmerman, MD, FACE

11

Comprehensive Goals For Diabetes Control-

Individualized

A1C Goals AACE (ADA)

≤6.5% (≤6.9%) for most; provided safely

Less than 6% as close to 5%(<6.5% ) for newly

diagnosed, relatively young, healthy; provided safely

≥6.5% (7.5/8/8.5 %) - Less stringent for “less healthy” –

multiple co-morbidities, labile, short life expectancy.

Blood Pressure: 130/80 (140/90) - General; 120/80 with

CKD or stroke risk; >140/90 - Hypotension/dizzy Risk

Lipids : < 100 – General risk; < 70 – High risk;

< 55 Extreme Risk (statin to all)

Handelsman Y et al, AACE/ACE Diabetes Guidelines, Endocr Pract. 2015;21(Suppl 1

Principles of AACE/ACE 2016 Diabetes Algorithms for Glycemic Control

• Comprehensive approach addressing all CV risk factors

• Minimize risk of hypoglycemia

• Minimize risk of weight gain

• Individualize and personalize management plan

• Consider both fasting and postprandial glucose levels

• Consider total cost of therapy, not just acquisition cost of the drug

– Hypoglycemic events

– Drug-related adverse events

– Treatment of complications from nonadherence

– Additional laboratory tests

• Include all major classes of FDA-approved glycemic medications

• Select therapy stratified by A1c level and by A1c-lowering potential

Rodbard HW et al. Endocr Pract. 2009;15:540-59. Garber AJ et al. Endocr Pract. 2013;19(suppl 2):1-48.

Hyperglycemia

β α

Treatment based on pathophysiology

INSULIN

RESISTANCE

↑glucose reabsorption

↓insulin 50-

80% at

diagnosis

↑Hepatic glucose

production

Decreased incretineffect 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

InsulinInsulin

TZDs

GLP-agonists

DPP IV inhibitors

Metformin

1. Better glucose control

2. Better blood pressure control

3. Better lipid control

4. All are important

5. Only blood pressure and lipids control

Case Jack: Discussion points 1

Which factor is most important with respect to preventing recurrent CAD events ?

How should the dyslipidemia be approached? Simvastatin 20mg QD TGL- 233; LDL-138; HDL- 34; Lp (a) 36


1. Wait until better glucose control is achieved

2. Increase dose of statin / change statin

3. Combine statin with fibrate

4. Combine statin with ezetimibe

5. Combine statin with omega-3 fatty acids

6. Add PCSK9i

7. Other Combinations

How should the HTN be approached?

Currently on Ramipril 5mg QD BP- 145/88


1. Increase Ramipril 10mg

2. Switch to HCTZ

3. Add Aplodipine 5

4. Change to Losartan 50mg

5. Add Beta Blocker

6. 1 & 3

7. No Change

How should the hyperglycemia be approached?

Currently on Metformin 1000 mg QD A1C- 8.6%


1. Increase Metformin to 2000mg daily

2. Add GLP1-ra

3. Switch to DPP41

4. Add SGLT2i

5. Both 1 & 2

6. Switch to SU

7. Both 3 & 4

GLP-1 Receptor Agonists

FDA-Approved Agents

• Lixisenatide

• Dulaglutide

• Exenatide

• Exenatide ER

• Liraglutide

• Semaglutide

Key Features

• Injectable administration

• Mimic action of native GLP-1

• Increase glucose-dependent

insulin secretion

• Suppress Endogenous

Glucose production

• Reduces glucagon Level

• 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

Antihyperglycemic Activities of GLP1-ra

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

cebo

-adju

ste

d

A

1C

(%

)

‡

‡

‡ ‡

‡

‡

‡

‡


Alb1 Dul2 Exe3 Exe

ER4


ER9


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 (k

g)

Absolute Change from Baseline


Blood Pressure Changes

With LiraglutideMonotherapy 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)

*

*

*

*


Alb1 Dul2 Exe3 Exe

ER4


ER9


ER13,†

Lir14

Hypoglycemia with GLP-1

Receptor Agonists

03

10.412.3

9

36

4.0 5.0

13.0

5.21

8.18

3

0

5

10

15

20

25

30

35

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


Patients

(%

)

-2.0

-1.5

-1.0

-0.5

0.0

Change fro

m b

aseline

in H

bA

1c(%

)

Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo Sitagliptin 100 mg Exenatide ER 2.0 mg IGlar

–1.5–1.6

–1.3

–1.6

–0.5

–1.5

–0.9

–1.2

–1.6

–0.8

–1.4

–1.8

–0.1<–0.1

Semaglutide- SUSTAIN 1–5: change in HbA1c

*p<0.0001 vs comparator. Exenatide ER, exenatide extended release; IGlar, insulin glargine.Ahmann A et al. Presented at the 77th Scientific Sessions of the American Diabetes Association, 9–13 June 2017, San Diego, CA, USA. Poster Number 1080-P.

SUSTAIN 1monotherapy

SUSTAIN 2vs sitagliptin

SUSTAIN 3vs exenatide ER

SUSTAIN 4vs IGlar

SUSTAIN 5add-on to basal insulin

Treatment duration: 30 weeks 56 weeks 56 weeks 30 weeks 30 weeksHbA1c at baseline: 8.1% 8.1% 8.3% 8.2% 8.4%

**

*

**

*

*

*

*

-8.0

-7.0

-6.0

-5.0

-4.0

-3.0

-2.0

-1.0

0.0

1.0

2.0

Change fro

m b

aseline (

kg)

Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo Sitagliptin 100 mg Exenatide ER 2.0 mg IGlar

–3.7

–4.5

–1.0

–4.3

–6.1

–1.9

–5.6

–1.9

–3.5

–5.2

1.2

–3.7

–6.4

–1.4

Semaglutide- SUSTAIN 1–5: change in body weight

*p<0.0001 vs comparator. BW, body weight; exenatide ER, exenatide extended release; IGlar, insulin glargine.Lingvay I et al. Presented at the 77th Scientific Sessions of the American Diabetes Association, 9–13 June 2017, San Diego, CA, USA. Oral presentation 243-OR.

SUSTAIN 1monotherapy

SUSTAIN 2vs sitagliptin

SUSTAIN 3vs exenatide ER

SUSTAIN 4vs IGlar

SUSTAIN 5add-on to basal insulin

Treatment duration: 30 weeks 56 weeks 56 weeks 30 weeks 30 weeksBW at baseline: 92 kg 89 kg 96 kg 93 kg 92 kg

*

* *

**

*

*

*

*

Safety Considerations

with GLP1 Receptor AgonistsGI 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.

Jane• 54 yrs old woman comes for second Opinion

– Type 2 diabetes for 6.5 yrs, 2 yrs ago MI.

– Recently hospitalized for dyspnea diagnosed with CHF, now stable

– ROS: Fatigue, sleep disturbance, joint pain

– Social: office manager, Diet- Variable; exercise-none. Married, 2 adult children. Fx Hx- DM, CVD

– SMBG: 120–170 mg, mostly fasting.

– Medications: Lisinopril 10mg, torsemide 10, Atenolol 25, Metformin 1000mg BID, Atorvastatin 40mg daily

Jane: Physical Exemination: BMI 32.5; Blood

Pressure 138/87; H. R.- 84;

Lab Test Results

BUN- 22, Cr – 1.1 eGFR- 76

Urinary albumin - 20 mcg/min

A1C - 7.7%

Lipid : TC 189 LDL 112, HDL 42, TG 175

Jane: Blood Pressure Control 138/87

Med:Lisinopril 10mg, Atenolol, DiureticGoal: <130/80Consider:: Lisinopril 40mg

Lipid ControlTC 189 LDL 112 HDL 42 TG 175Med: Atorvastatin 40mgGoal LDL: <55 mg/dlConsider: Atorva 80, Combination with Ezetimibe, PCSK9i, BAS, niacin

Jane: Glycemic ControlA1C: : 7.7% Med: : Metformin 1000 BID

What should be Jane’s A1C goal

A. < 7%

B. < 7.5%

C. > 8 %

D. < 6.5 %

E. The goal should be Glucose not A1C

Jane’s Glucose Control- Add:

36

A. Sulfonylurea

B. DPP4i

C. GLP1-ra

D. SGLT2-i

E. Insulin

F. B & C

G. C & D

H. No Change

SGLT2 InhibitorsCanagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin

Invokana [Package Insert] Janssen Pharmaceuticals, Inc. Titusville, NJ.; Lavalle-gonzález FJ, Januszewicz A, Davidson J, et al. Diabetologia. 2013; StenlöfK, 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 On Average A1C 0.7-1.1%

AdvantagesInsulin-independent glucose reduction, Low risk of hypoglycemia, Weight loss (to 4% BW), Blood pressure-lowering

Disadvantages

Mild osmotic diuresis, initial Polyuria, potential lightheadedness, Genital Micotic infections (females≈10%), Increased LDL cholesterol,

ContraindicationsSevere kidney disease eGFR < 30 mL/min/1.73 m²

Glucose

Proximal tubuleS1 segment

SGLT2~90% glucose reabsorption

SGLT-1~10% glucose reabsorption

S3 segment

Collectingducts

SGLT 2 Inhibitors A1c ↓ 0.7-1.1%

Sodium-glucose co-transporter 2 inhibitors (SGLT2)

Benefits :

•Weight loss

•Improved systolic BP

•A1c reduction

Other effects

•Increase LDL

•Increase risk of yeast

infections

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

Ertuglflozin

(Steglatro 5 & 15 mg)

GFR>60 mL/min/1.73m²

Glucose Control

with SGLT2 InhibitorsPlacebo-Adjusted Change from Baseline


*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

juste

d

A

1C

(%

)

*

*

1.1

-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

Ertugliflozin Mono: Change in A1C Over Time

Ertugliflozin + MET: Change in A1C over Time

A1C

(%

) C

hange f

rom

Baselin

e (

LS

Mean, ±

SE

)

Ertugliflozin + Sita: Change in A1C

Weight Change

with SGLT2 InhibitorsAbsolute Change from Baseline


W

eig

ht

(kg

)



-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





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, 201445

-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

46

Absolute Change from Baseline


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.



-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

ys

toli

c B

P (

mm

Hg

)

Hypoglycemia with SGLT2 Inhibitors

Percentage of Patients Reporting Hypoglycemia








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

Time course of eGFR (meta-analysis)

48

Changes in eGFR

4 8 16 24 37 501 63 76 89 102 (Week)BL

Number of patients

Placebo (n=1,955)

Ch

an

ge f

rom

baseli

ne 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 mg81.0

80.7

EMDAC data

<http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/

endocrinologicandmetabolicdrugsadvisorycommittee/ucm378079.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)

EQW + DAPA Significantly Reduced A1C at Week 28

49

* Difference, p<0.05 vs. EQW; † Difference, p<0.05 vs. DAPA; ‡ Difference, p=0.004; § Difference, p<0.001.

Note: Data is least squares mean change. Error bars show standard errors. Analyzed in the ITT population.

Frὶas JP, et al. Lancet Diabetes Endocrinol. 2016. Accessed September 16, 2016. In House Data, AstraZeneca Pharmaceuticals LP. CSR D5553C00003.

EQW + DAPA (n=228); BL, 9.3%

EQW (n=227); BL, 9.3%

DAPA (n=230); BL, 9.3%

-1.6%

-1.4%

-2.0%

-0.4%‡

-0.6%§

0.0

-0.5

-1.0

-1.5

-2.0

-2.5

0 4 8 12 16 20 24 28

Ch

an

ge i

n A

1C

, %

Time (weeks)

*

†

*

†

*

†*

†

*

†

*

†

*

†

EQW + DAPA Significantly Reduced Weight from Baseline at Week 28

50

* Difference, p<0.05 vs. EQW; † Difference, p<0.05 vs. DAPA; ‡ Difference, p=0.002; § Difference, p=0.002.

Note: Data is least squares mean change. Error bars show standard errors. Analyzed in the ITT population.


-1.54 kg

-2.19 kg

-3.41 kg

-1.22

kg‡

-1.87

kg§

0

-0.5

-1.5

-3.0

-3.5

-4.5

0 4 8 12 16 20 24 28

Ch

an

ge i

n W

eig

ht,

kg

Time (weeks)

-4.0

-2.5

-1.0

1 2

-2.0

*

EQW + DAPA (n=228); BL, 91.8 kg

EQW (n=227); BL, 89.8 kg

DAPA (n=230); BL, 91.1 kg

*

*

*

†

*

†

*

†

*

†*

†*

†

EQW + DAPA Significantly Reduced SBP from Baseline at Week 28

51

* Difference, p<0.05.

Note: Data is least squares mean change. Analyzed in the ITT population.


EQW + DAPA EQW DAPA

–2.9 mm Hg*

–2.4 mm Hg*

BL, mm Hg 130.5 129.6 129.7

Xultophy: combination therapy for the treatment

of type 2 diabetesKEY POINTS Xultophy is an injection combining insulin degludec

with liraglutide for T2D 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

iGlarLixi, single-injection fixed-ratio combination of GLP1-RA &

Analog Basal Insulin- lixisenatide (Adlyxin) & Glargine (Lantus)"Improved Glucose Control without Increased Hypoglycemia Risk at Any Level of

HbA1c Reduction with Insulin Glargine/Lixisenatide Fixed-Ratio Combination (Soliqua)

vs. Insulin Glargine Alone Both Added On to Metformin in Type 2 Diabetes (T2DM)"

Study SAVOR EXAMINE TECOS CAROLINA CARMELINA

DPP4-i saxagliptin alogliptin sitagliptin linagliptin linagliptin

Comparator 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 REWIND FREEDOM

GLP1-RA liraglutide lixisenatide semaglutide exenatide LR dulaglutide ITCA-650

Comparator placebo placebo placebo NEUTRAL 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

Comparator placebo POSITIVE placebo placebo

N 7300 4300 22,200 3900

Results Sept 2015 2017 2019 2020

Large non-insulin CVOTs in T2DM

NEUTRAL NEUTRAL NEUTRAL

NEUTRAL

+ +

NEUTRAL

+

POSITIVE

POSITIVEPOSITIVE

Study ORIGIN DEVOTE

Basal

Insulin

Glargine Degludec

Comparator Standard of

Care

Glargine

N 12,500 7,600

Results 2012 2016

Large Insulin CVOTs in T2DM

✓ ✓

LEADER- Primary outcomeCV 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.

Time to first renal eventMacroalbuminuria, 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.

• Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes

• To reduce the risk of major adverse CV events (CV death, non-fatal MI, or non-fatal stroke) in adults with type 2 diabetes mellitus and established CV disease

• Not for treatment of type 1 diabetes or diabetic ketoacidosis

• Has not been studied in combination with prandial insulin

Indications and usage

Victoza® [package insert]. Princeton, NJ: Novo Nordisk Inc.; August 2017

Contraindications

• Liraglutide is contraindicated in patients with:• Personal or family history of MTC or MEN2

• History of serious hypersensitivity to liraglutide or any product component

Initiate dosing at 0.6 mg/day for 1 week to reduce GI

symptoms

Increase dose to 1.2 mg/day after 1

week

Increase dose to 1.8 mg/day, if 1.2 mg does not result in

acceptable glycemic control

Dose initiation and titration

Limitations of use

Not recommended as first line language removed

Language “not studied in patients with hx of pancreatitis – consider other antidiabetic therapies” removed. Added “unknown if patients with a hx of pancreatitis are a higher risk of pancreatitis with Victoza”

Warnings and Precautions: Added “Acute Gallbladder disease: if cholelithiasis or cholecystitis are suspected, gallbladder sutdies are indicated”

Liraglutide- New Indication post LEADER

Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1607141

Sustain 6: Cardiovascular Outcomes

EMPA-REG

Primary outcome: 3-point MACE

59

HR 0.86

(95.02% CI 0.74, 0.99)

p=0.0382*

Cumulative incidence function. MACE, Major Adverse

Cardiovascular Event; HR, hazard ratio.

* Two-sided tests for superiority were conducted (statistical

significance was indicated if p≤0.0498)

EMPA-REG: Renal function over time

BL, baseline; PBO, placebo; EMPA, empagliflozin; FU, follow-up; LMDT, last measurement during treatment. Wanner C et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1515920.

78

76

74

72

70

68

66

BL 4 12 28 52 66 80 94 108 122 136 150 164 178 192Week

Adju

ste

d m

ean e

GFR

(ml/

min

/1.7

3m

2) Change In eGFR Over 192 Weeks

No. at Risk:PBO 2323 2295 2267 2205 2121 2064 1927 1981 1763 1479 1262 1123 977 731 448EMPA 10mg 2322 2290 2264 2235 2162 2114 2012 2064 1839 1540 1314 1180 1024 785 513EMPA 25mg 2322 2288 2269 2216 2156 2111 2006 2067 1871 1563 1340 1207 1063 838 524

Placebo

EMPA 10mg

EMPA 25mg

Primary MACE Outcome CANVASCV Death, Nonfatal Myocardial Infarction or Nonfatal Stroke

2 3 4

Years since randomization

5 61

Hazard ratio 0.86 (95% CI, 0.75-0.97) p <0.0001 for noninferiority

p = 0.0158 for superiority

20

18

16

14

12

10

8

6

4

2

0

0

Pati

en

tsw

ith

an

even

t (%

)

Placebo

Canagliflozin

No.ofpatients

Placebo 4

Canagliflozin 5

347 4153 2942 1240 1187 1120 789

795 5566 4343 2555 2460 2363 1661

Intent-to-treat analysis

Composite of 40% Reduction in eGFR, End-stage Renal Disease, or Renal Death

4227 3029 1274 1229 1173 8195664 4454 2654 2576 2495 1781

347795

Hazard ratio 0.60 (95% CI, 0.47-0.77)

Events (n)

40% eGFR reduction 239

End-stage renaldisease/renal death

21

Intent-to-treat analysis

No.ofpatients

Placebo 4Canagliflozin 5

0 1 5 6

20

18

16

14

12

10

8

6

4

2

0

2 3 4

Years since randomization

Pati

en

tsw

ith

an

even

t (%

)

Placebo

Canagliflozin

Hazard ratio (95% CI)

1.0 2.0

Favors Placebo

0.5

Favors SGLT2i

CV death, nonfatal myocardial infarction, or nonfatal stroke

Key Outcomes in the CANVAS Programand EMPA-REG OUTCOME

*CANVAS Program endpoints comparable with EMPA-REG OUTCOME.

0.25

Zinman Bet al. N Engl J Med. 2015 ;373(22):2117-2128. Wanner K et al. N Engl J Med. 2016;375(4):323-334.

CANVAS Program

EMPA-REG OUTCOME

CV death

Nonfatal myocardial infarction Nonfatal

stroke

Hospitalization for heart failure

CV death or hospitalization for heart

failure All-cause mortality

Progression to macroalbuminuria*

Renal composite*

Kosiborod M et al. Circulation. 2017; doi.org/10.1161/CIRCULATIONAHA.117.029190

CVD Real- Data sources

Cohort 2All-cause death

and composite

HHF/all-cause

death

Cohort 1HHF

US

• Truven Health MarketScan Claims and Encounters and linked Medicare Supplemental and Coordination of Benefits (Medicare Supplemental) databases

Norway

• Linked Prescribed Drug, National Patient and Cause of Death Registries

Sweden


Denmark


UK

• Clinical Practice Research Datalink (CPRD) dataset

• The Health Improvement Network (THIN) dataset

Germany

• Diabetes-Patienten-Verlaufsdokumentation (Diabetes Prospective Follow-Up; DPV)

Even

t R

ate

per

100

Pati

en

t-Y

ears

Established


Heart Failure Heart Failure Heart Failure

or

Death

Heart Failure

or

Death

Death Death

No Known


p<0.001 for all comparisons

SGLT-2i

oGLDSGLT-2i

oGLD

CVReal: Absolute Rates of CV Events in Patients reated with SGLT-2i- Secondary & Primary Prevention

Cavender M at al.. Presented at ADA Scientific Sessions; June 9 – May 13, 2017; San Diego, CA.

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 GLP1ra and SGLT2i as first options with metformin based on safety efficacy in reducing glucose and positive effect on CV risk parameters especially weight and blood pressure

66

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AACE Diabetes Algorithm- Focus on: SGLT2-inhibitors and ...syllabus.aace.com/2018/PCP/ShermanOaks... · Yehuda Handelsman, MD, FACP, FNLA, MACE Courtyard by Marriott, Saturday, April