Update on Novel Therapies in Diabetes:What’s Hot and What’s New?

Ronald M. Goldenberg, MD, FRCPC, FACEConsultant Endocrinologist,

LMC Diabetes and Endocrinology Vaughan, Ontario, Canada

Learning Objectives

At the conclusion of this activity, participants will:

• Know the efficacy, safety and clinical trial data for the following new or emerging novel therapies appropriate for diabetes patients:❖ Oral semaglutide

❖ Icosapent ethyl

❖Tirzepatide

SNAC: Sodium N-(8-(2-hydroxybenzoyl) amino) caprylate.1. Buckley ST et al. Sci Transl Med 2018;10:eaar7047.doi:10.1126/scitranslmed.aar7047.

Oral Semaglutide

Absorption of semaglutide in the stomach requires

co-formulation with the absorption enhancer SNAC

SNAC causes a local increase of pH leading to higher solubility and protection of semaglutide from

proteolytic degradation and increased transcellular absorption via gastric

epithelium

*OD, once daily. Hauge, C., et al. Endocrine Society (ENDO) – 101st Annual Meeting and Expo. 2019: New Orleans, USA.

Oral semaglutide dosing and administration

• No dose adjustment is required for drugs taken with oral semaglutide• Monitoring of thyroid parameters should be considered when treating patients with

oral semaglutide at the same time as levothyroxine

3mg

Start with 3 mg OD for 30 days

7mg

Increase dose to 7 mg OD for at least 30 days

14mg

Based on individual needs, you may increase

dose to 14 mg OD

STARTING DOSE MAINTENANCE DOSES

30 min

Dosing

Administration

Drug-Drug Interactions

Take on an empty stomach upon waking

Take with a sip of water (no more than 120 mL)

Wait at least 30 minutes before eating, drinking, or taking any

other oral medication

8.0 8.1 8.3 8.0 8.0 8.3 8.2Sema3 mg

Sema7 mg

Sema14 mg

Pbo Sema 14 mg

Empa25 mg

Sema3 mg

Sema7 mg

Sema 14 mg

Sita100 mg

Sema14 mg

Lira1.8 mg

Pbo Sema14 mg

Pbo SemaFlex

Sita100 mg

Sema3 mg

Sema7 mg

Sema14 mg

Pbo

PIONEER 1Monotherapy

26 weeks

PIONEER 2vs empagliflozin

26 weeks

PIONEER 3vs sitagliptin

26 weeks

PIONEER 4vs liraglutide

26 weeks

PIONEER 5Renal

26 weeks

PIONEER 7Flex†

52 weeks

PIONEER 8With insulin

26 weeks

CHANGE IN A1C – TREATMENT POLICY ESTIMAND – PRIMARY ENDPOINT

PIONEER 1–5, 7 and 8

Baseline A1C, %

-0.9

-1.2

-1.4

-0.3

-1.3

-0.9

-0.6

-1.0

-1.3

-0.8

-1.2-1.1

-0.2

-1.0

-0.2

-1.3

-0.8

-0.6

-0.9

-1.3

-0.1

-2.0

-1.5

-1.0

-0.5

0.0

Change in A

1C (

%)

*

*

**

*

*

* vs placeboWk 52: Sema -1.2*

Lira -0.9Pbo -0.2

*

*

*

*

*

‡

*Statistically significantly greater compared with placebo or active comparator. †Primary endpoint in PIONEER 7, subjects ach ieving A1C <7.0%. ‡Statistically significantly in favor of sitagliptin 100 mg compared with oral semaglutide 3 mg. Flex, flexible; Empa, empagliflozin; Lira, liraglutide; Pbo, placebo; Sema, semaglutide; Sita, sitagliptin. Aroda VR et al. Poster 2-LB. ADA 78th Annual Scientific Sessions. June 24, 2018; Montanya E, et al. Oral presentation 54-OR. ADA 79th Annual Scientific Sessions. June 08, 2019; Rosenstock J et al. JAMA 2019;321:1–15; Pratley R, et al. Lancet 2019. doi: 10.1016/S0140-6736(19)31271-1; Mosenzon O, et al. Lancet Diabetes Endocrinol 2019. doi: 10.1016/S2213-8587(19)30192-5; Husain M, et al. N Engl J Med

2019. doi: 10.1056/NEJMoa1901118; Pieber TR, et al. Lancet Diabetes Endocrinol 2019. doi: 10.1016/S2213-8587(19)30194-9;Zinman B, et al. Poster 985-P. ADA 79th Annual Scientific Sessions. June 10, 2019.

Oral semaglutide demonstrated significantly greater A1C lowering vs empagliflozin and sitagliptin and was noninferior to liraglutide at 26 weeks but superior at 52 weeks

CHANGE IN BODY WEIGHT – TREATMENT POLICY ESTIMAND

PIONEER 1–5, 7 and 8

Sema3 mg

Sema7 mg

Sema14 mg

Pbo Sema 14 mg

Empa25 mg

Sema3 mg

Sema7 mg

Sema 14 mg

Sita100 mg

Sema14 mg

Lira1.8 mg

Pbo Sema14 mg

Pbo SemaFlex

Sita100 mg

Sema3 mg

Sema7 mg

Sema14 mg

Pbo

PIONEER 1Monotherapy

26 weeks

PIONEER 2vs empagliflozin

26 weeks

PIONEER 3vs sitagliptin

26 weeks

PIONEER 4vs liraglutide

26 weeks

PIONEER 5Renal

26 weeks

PIONEER 7Flex

52 weeks

PIONEER 8With insulin

26 weeks

88.1 (194.2) 91.6(201.9) 91.2 (201.1) 94.0 (207.2) 90.8 (200.2) 88.6 (195.3) 85.9 (189.4)Baseline body weight, kg (lbs)

-1.5

-2.3

-3.7

-1.4

-3.8 -3.7

-1.2

-2.2

-3.1

-0.6

-4.4

-3.1

-0.5

-3.4

-0.9

-2.6

-0.7

-1.4

-2.4

-3.7

-0.4

-6.0

-5.0

-4.0

-3.0

-2.0

-1.0

0.0

*

*

*

*

*

*

*

*

*

*

Change in b

ody w

eig

ht

(kg)

*Statistically significantly greater compared with placebo or active comparator. Flex, flexible; Empa, empagliflozin; Lira, liraglutide; Pbo, placebo; Sema, semaglutide; Sita, sitagliptin. Aroda VR et al. Poster 2-LB. ADA 78th Annual Scientific Sessions. June 24, 2018; Montanya E, et al. Oral presentation 54-OR. ADA 79th Annual Scientific Sessions. June 08, 2019; Rosenstock J et al. JAMA2019;321:1–15; Pratley R, et al. Lancet 2019. doi: 10.1016/S0140-6736(19)31271-1; Mosenzon O, et al. Lancet Diabetes Endocrinol 2019. doi: 10.1016/S2213-8587(19)30192-5; Husain M, et al. N Engl J Med 2019. doi: 10.1056/NEJMoa1901118; Pieber TR, et al. Lancet Diabetes Endocrinol 2019. doi: 10.1016/S2213-8587(19)30194-9; Zinman B, et al. Poster 985-P. ADA 79th Annual

Scientific Sessions. June 10, 2019.

Oral semaglutide demonstrated significantly greater weight reductions vs sitagliptin and liraglutide and was similar to empagliflozin

0

10

20

30

40

50

Sema3 mg

Sema7 mg

Sema14 mg

Pbo Sema 14 mg

Empa25 mg

Sema3 mg

Sema7 mg

Sema 14 mg

Sita100 mg

Sema14 mg

Lira1.8 mg

Pbo Sema14 mg

Pbo SemaFlex

Sita100 mg

Sema3 mg

Sema7 mg

Sema14 mg

Pbo

PIONEER 1Monotherapy

26 weeks

PIONEER 2vs empagliflozin

52 weeks

PIONEER 3vs sitagliptin

78 weeks

PIONEER 4vs liraglutide

52 weeks

PIONEER 5Renal

26 weeks

PIONEER 7Flex

52 weeks

PIONEER 8With insulin

52 weeks

PROPORTION OF PATIENTS WITH NAUSEA

PIONEER 1–5, 7, 8

Empa: empagliflozin; Lira: liraglutide; Pbo: placebo; Sema: semaglutide; Sita: sitagliptin.

Pro

port

ion o

f patients

(%

)

8.0

5.1

16.0

5.6

19.8

2.4

7.3

13.415.1

6.9

19.618.0

3.5

19.0

7.5

20.9

2.4

11.4

16.6

23.2

7.1

Overall safetyOral semaglutide was well-tolerated with a safety profile consistent with the GLP-1RAs class. The most common adverse

event was mild to moderate nausea

Aroda VR et al. Poster 2-LB. ADA 78th Annual Scientific Sessions. June 24, 2018; Montanya E, et al. Oral presentation 54-OR. ADA 79th Annual Scientific Sessions. June 08, 2019; Rosenstock J et al. JAMA 2019;321:1–15; Pratley R, et al. Lancet 2019. doi: 10.1016/S0140-6736(19)31271-1; Mosenzon O, et al. Lancet Diabetes Endocrinol 2019. doi: 10.1016/S2213-8587(19)30192-5; Husain M, et al. N Engl J Med

2019. doi: 10.1056/NEJMoa1901118; Pieber TR, et al. Lancet Diabetes Endocrinol 2019. doi: 10.1016/S2213-8587(19)30194-9;Zinman B, et al. Poster 985-P. ADA 79th Annual Scientific Sessions. June 10, 2019.

CARDIOVASCULAR ENDPOINTS

PIONEER 6

CI, confidence interval; CV, cardiovascular; EAC, event adjudication committee; HF, heart failure; HR, hazard ratio; MI, myocardial infarction; MACE, major adverse cardiovascular events. Husain M et al. N Engl J Med 2019;381:841–51.

0 9 18 27 36 45 54 63 72 830

1

2

3

4

5

6

Time from randomization (weeks)

Patients

with a

n e

vent

(%) HR: 0.79 [0.57–1.11]

P<0.001 non-inferiorityP=0.17 superiority

Primary outcome: Time to first MACE

Oral semaglutide Placebo

Median duration: 15.9 months

76 (4.8%)

61 (3.8%)

Favours placebo

Favours oral semaglutide

Hazard Ratio (95% CI)

Primary analysis: MACE (137 events) 0.79 [0.57–1.11]

Expanded MACE (183 events) 0.82 [0.61–1.10]

CV death (45 events) 0.49 [0.27–0.92]

Non-fatal MI (68 events) 1.18 [0.73–1.90]

Non-fatal stroke (28 events) 0.74 [0.35–1.57]

All-cause death (68 events) 0.51 [0.31–0.84]

Unstable angina requiring hospitalization (18 events)

1.56 [0.60–4.01]

HF requiring hospitalization (45 events)

0.86 [0.48–1.55]

0.25 1 4

Key secondary outcomes:

Cardiovascular safetyConfirmed for oral semaglutide in PIONEER 6, showing a 21% non-significant reduction in MACE in favor of oral semaglutide compared with placebo. Ongoing SOUL trial powered for CV superiority

Icosapent Ethyl

Icosapent ethyl is a highly purified and stable ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA) and requires a prescription

Rationale for the Use of Highly Purified Eicosapentaenoic Acid (EPA)

• EPA and Docosahexaenoic acid (DHA) have different properties and distinct membrane locations1

➢ Purified EPA has demonstrated potent antioxidant and anti-inflammatory effects1

➢ DHA associated with modest LDL-C elevation while EPA is LDL-C neutral

• Sources for EPA and DHA include fish/seafood, omega-3 fatty acid supplements and fortified foods

• Contemporary trials (ASCEND2, VITAL3, STRENGTH4) and meta-analyses5 of mixed EPA/DHA omega-3 fatty acid products at doses from 1-4 g daily have not shown a CV benefit in patients receiving statins

• JELIS demonstrated a reduction in major coronary events with EPA 1.8 g plus statin vs statin alone6

• Icosapent ethyl lowers TGs by 22% in statin treated patients with TG in 2.3 to <5.6 mmol/L range7

1. Sherratt SCR et al. Chem Phys Lipids 2018;212:73-79. 2. Bowman L et al. NEJM 2018;379:1540-1550. 3. Manson JE et al. NEJM 2019;380:23-32. 4. https://www.astrazeneca.com/media-centre/press-releases/2020/update-on-phase-iii-strength-trial-for-epanova-in-mixed-dyslipidaemia-13012020.html

5. Aung T et al. JAMA Cardiol 2018;3:225-234. 6. Yokoyama M et al. Lancet 2007;369:1090-1098. 7.Ballantyne CM et al. Am J Cardiol 2012;110:984-992.

(≥1.7 to <5.6 mmol/L)

(>1.0 to <2.6 mmol/L)

(≥1.5 mmol/L)

REDUCE-IT Design

~59% had DM:~29% established DM & CVD~29% DM & primary prevention

**Risk factors: male ≥55, female ≥65; smoking; hypertension; HDL <1.0 male, <1.3 female; hsCRP>3; CrCl 30-60; albuminuria; retinopathy; ABI <0.9

**

Biomarker*

Baseline

Median

Median Between Group Difference at year 1

% Change

from

Baseline

% Change

P-value

Triglycerides (mmol/L) 2.4 -19.7 <0.0001

Non-HDL-C (mmol/L) 3.1 -13.1 <0.0001

LDL-C (mmol/L) 1.9 -6.6 <0.0001

HDL-C (mmol/L) 1.0 -6.3 <0.0001

Apo B (g/L) 0.83 -9.7 <0.0001

hsCRP (mg/L) 2.2 -39.9 <0.0001

Log hsCRP (mg/L) 0.8 -22.5 <0.0001

EPA (µg/ml) 26.1 +385.8 <0.0001

Biomarkers at Baseline and Percent Change at Year 1

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2019; 380:11-22.

Bhatt DL. ACC/WCC 2020, Chicago (virtual).

*Apo B and hsCRP were measured at Year 2.

Primary End Point:CV Death, MI, Stroke, Coronary Revasc, Unstable Angina

Icosapent Ethyl

23.0%Placebo

28.3%

Years since Randomization

Pati

en

ts w

ith

an

Eve

nt

(%)

0 1 2 3 4 5

0

10

20

30

P=0.00000001

RRR = 24.8%

ARR = 4.8%

NNT 4.9y = 21 (95% CI, 15–33)

Hazard Ratio, 0.75(95% CI, 0.68–0.83)

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2019. Bhatt DL. AHA 2018, Chicago.

Bhatt DL et al. JACC 2019;74:1159-1161. Bhatt DL. ACC/WCC 2020.Chicago (virtual)

Consistent efficacy across multiple subgroups:Risk category (secondary or primary prevention)Diabetes (diabetes or no diabetes)Baseline TG (<1.7 or ≥ 1.7)Baseline TG by tertiles (0.9-2.1/>2.1-2.8/>2.8-15.8)Achieved TG (< 1.7 or ≥ 1.7)

Benefit beyond what can be explained by TG loweringOn-treatment EPA levels via icosapent ethyl correlate strongly with the primary endpoint

17.2%

22.0%

20.0%

16.2%

Icosapent Ethyl

Placebo

Key Secondary End Point:CV Death, MI, Stroke

Hazard Ratio, 0.74(95% CI, 0.65–0.83)

RRR = 26.5%

ARR = 3.6%

NNT 4.9y = 28 (95% CI, 20–47)

P=0.0000006

Years since Randomization

Pati

en

ts w

ith

an

Eve

nt

(%)

0 1 2 3 4 5

0

10

20

30

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2019. Bhatt DL. AHA 2018, Chicago.

Bhatt DL. ACC/WCC 2020, Chicago (virtual)

Consistent efficacy across multiple subgroups: Risk category (secondary or primary prevention)Diabetes (diabetes or no diabetes)Baseline TG (<1.7 or ≥ 1.7)Achieved TG (< 1.7 or ≥ 1.7)

Benefit beyond what can be explained by TG loweringOn-treatment EPA levels via icosapent ethyl correlate strongly with the secondary endpoint

14.8%

11.2%

Treatment-Emergent Adverse Eventof Interest: Bleeding

Icosapent Ethyl

(N=4089)

Placebo

(N=4090) P-value

Any bleeding event

Serious bleeding related disorders

482 (11.8%)

111 (2.7%)

404 (9.9%)

85 (2.1%)

0.006

0.06

Gastrointestinal bleeding 62 (1.5%) 47 (1.1%) 0.15

Central nervous system bleeding 14 (0.3%) 10 (0.2%) 0.42

Other bleeding 41 (1.0%) 30 (0.7%) 0.19

• No fatal bleeding events in either group

• Adjudicated hemorrhagic stroke - no significant difference between treatments

(13 (0.3%) icosapent ethyl versus 10 (0.2%) placebo; P=0.55)

• Bleeding was greater in patients receiving concomitant antithrombotic medications, such

as aspirin, clopidogrel, or warfarin (approx. 13% icosapent ethyl vs 11% placebo)

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2019; 380:11-22.

Vascepa Canadian Product Monograph; December 30, 2019.FDA Ad Com Nov. 14, 2019. FDA Briefing Document.

Adjudicated Events: Hospitalization for Atrial Fibrillation or Atrial Flutter

Primary System Organ Class

Preferred Term

Icosapent

Ethyl

(N=4089)

Placebo

(N=4090) P-value

Positively Adjudicated Atrial

Fibrillation/Flutter[1] 127 (3.1%) 84 (2.1%) 0.004

Note: Percentages are based on the number of subjects randomized to each treatment group in the Safety population (N).

All adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA Version 20.1).

[1] Includes positively adjudicated Atrial Fibrillation/Flutter clinical events by the Clinical Endpoint Committee (CEC). P value was based

on stratified log-rank test.

Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2019; 380:11-22.

Icosapent Ethyl Indications and Dosage in Canada

Indications:

Icosapent ethyl is indicated to reduce the risk of cardiovascular events (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization or hospitalization for unstable angina) in statin-treated patients with elevated triglycerides*, who are at high risk of cardiovascular events due to:

• established cardiovascular disease, or

• diabetes, and at least one other cardiovascular risk factor.

Dosage:

4 grams per day, taken as two 1 g capsules twice a day with food

Vascepa Canadian Product Monograph; December 30, 2019.

* Triglycerides ≥ 1.5 mmol/L at screening in REDUCE-IT

Tirzepatide: A Novel Dual GIP and GLP-1R Agonist

Tirzepatide is a novel dual glucose-

dependent insulinotropic polypeptide

(GIP) and glucagon-like peptide-1

(GLP-1) receptor co-agonist. It is a

39 amino acid synthetic peptide that is

conjugated to a C20 fatty diacid

moiety and designed for once weekly

dosing.

Muler TD et al. Pharmacol Rev 2018;70:712-746.

Coskun T et al. Mol Metab. 2018;18:3-14.Tirzepatide is not approved by Health Canada

Tirzepatide: Phase 2b Trial Design and Key Findings

Data for change in HbA1c and bodyweight presented are LS mean ± SE from MMRM; modified intent-to-treat population excluding data after study drug discontinuation or rescue drug initiation. *p<0.05 vs. placebo

and #p<0.05 vs. dulaglutide 1.5 mg. 2. Frias et al. Lancet 2018;392:2180-2193.

Pbo 1 mg 5 mg 10 mg 15 mg Dula

3.9 3.8 9.1 5.9 24.5 11.1

Discontinued due to AEs (%)

Tirzepatide:

Phase 2 Study of 3 Dose Escalation Regimens

1. Frias J, et al. Diabetes Obes Metab 2020;10.1111/dom.13979

Tirzepatide Dosing in Phase 3

https://investor.lilly.com/webcasts-and-presentations

Tirzepatide Phase 3 Clinical Trial Program

https://investor.lilly.com/webcasts-and-presentations

Summary: Tirzepatide

• Tirzepatide is a dual GIP and GLP-1RA with A1C reduction and weight

loss beyond that of dulaglutide in patients with T2D

• The tolerability assessment within the different dose escalation steps

showed that a lower starting dose and smaller dose increments results

in fewer incidents of nausea, vomiting, and/or diarrhea and fewer

treatment discontinuations due to AEs

• The dose-escalation period was limited to 8 weeks in phase 2; longer dose

escalation may have resulted in further improvements in the incidence of

nausea, vomiting, and diarrhea.

• Phase 2 contributed to the starting dose and dose escalation regimen of the

SURPASS Phase 3 studies.