Ferhan Siddiqi, MD FRCPC MScHQAssistant Professor

Division of Endocrinology & Metabolism, QEII HSC (Central Zone)April 19, 2018

This speaker has been asked to disclose to the audience any involvement with industry or other organizations that may potentially influence the presentation of any educational material.

Receiving evaluations is critical to the accreditation process. After the program, please provide feedback at: https://surveys.dal.ca/opinio/s?s=41441

– Grants/Research Support: AstraZeneca Canada

– Speakers Bureau/Honoraria: None

– Consulting Fees: None

– Advisory Boards: Novo-Nordisk, Sanofi, Janssen, Abbott

– Funded Conferences: None

At the end of this talk, participants will be able to:

◦ Describe the impact of early tight glycemic control in the development of complications in type 2 diabetes (DM2)

◦ Outline various new glucose-lowering agents developed for use in type 2 diabetes including knowledge of their mechanism, efficacy and safety in treatment

◦ Individualize the selection of pharmacotherapy in patients with type 2 diabetes based on patient and agent-specific characteristics including cardiovascular (CV) outcomes

58 year-old man, tour operator

DM2 x 8 yr, MI age 54

A1c 8.7%

On metformin 1 g bid, gliclazide MR 120 mg daily, ramipril 5 mg daily, rosuvastatin 5 mg daily

BMI 34.3, BP 128/78, LDL 1.9

What would you recommend for him?

Pe

rce

nta

ge d

ecr

eas

e in

ris

k co

rre

spo

nd

ing

to a

1%

de

cre

ase

in A

1c

**

Any diabetes-related

endpoint

21%

**

Diabetes-related death

21% **

All-cause

mortality

14%

*

Stroke

12%

**

Peripheral vascular disease†

43%

**

Myocardialinfarction

14%

**

Micro-vascular disease

37%

**

Cataract extraction

19%

Observational analysis from UKPDS

† Lower extremity amputation or fatalperipheral vascular disease

* p=0.035; **p<0.0001

Stratton IM et al. BMJ 2000;321:405-12.

Holman RR et al. N Engl J Med. 2008;359:1577-89.

7.9%

7.0%

~ 8%Intensive therapy

Holman RR et al. N Engl J Med. 2008;359:1577-89.

Early glycemic control reduces the risk of latermicrovascular and macrovascular complications

17%reduction

13%reduction

15%reduction

24%reduction

Diabetes-related mortality

All-cause mortality

Myocardial infarction

Microvascularendpoints

2013

which must be balanced against the risk of hypoglycemia

Consider 7.1-8.5% if:

Can J Diabetes 2013;37(Suppl 1):S1-S212.

Leiter et al. Can J Diabetes. 2013;37:82-89.

Proportions of patients at various A1C strata* (DM-SCAN)

A1C 7% to ≤8%

28.5%

A1C >9%

9%

A1C ≤7%

50%

*≤7.0% was the goal set by physicians for 81% of patients

A1C 8% to ≤9%

12.5%

DM-SCAN survey of 5103 Canadians

with type 2 diabetes (2012)

50%

Start metformin immediately

Consider a second concurrent

antihyperglycemic agent

Start healthy behaviour interventions

(nutritional therapy, weight management, physical activity) +/- metformin

A1C <1.5% above targetSymptomatic hyperglycemia

and/or metabolic decompensationA1C 1.5% above target

Initiate insulin +/-

metforminIf not at glycemic target

within 3 months,

start/increase metformin

If not at glycemic target

HE

AL

TH

Y B

EH

AV

IOU

R I

NT

ER

VE

NT

ION

S

Clinical CVD?

See next page

AT DIAGNOSIS OF TYPE 2 DIABETES

2018

If not at glycemic target

YES

Start antihyperglycemic agent with

demonstrated CV benefit

empagliflozin (Grade A, Level 1A)

liraglutide (Grade A, Level 1A)

canagliflozin* (Grade C, Level 2)

NO

If not at glycemic target

* Avoid in people with prior lower extremity amputation

Add additional antihyperglycemic agent best suited to the individual based

on the following

Other considerations:

Reduced eGFR and/or albuminuria

Clinical CVD or CV risk factors

Degree of hyperglycemia

Other comorbidities (CHF, hepatic

disease)

Planning pregnancy

Cost/coverage

Patient preference

see Renal Impairment Appendix

See Table Below

CLINICAL CONSIDERATIONS CHOICE OF AGENT

Avoidance of hypoglycemia and/or

weight gain with adequate glycemic

efficacy

DPP-4 inhibitor, GLP-1 receptor

agonist or SGLT2 inhibitor

Clinical CVD?

NO

2018

If not at glycemic targets

Add another antihyperglycemic agent from a different class and/or add/intensify insulin regimen

Make timely adjustments to attain target A1C within 3-6 months

2018

2018

Add additional antihyperglycemic agent best suited to the individual by prioritizing patient characteristics (agents listed in alphabetical order by CV outcome data):

Class Effect on CVD Outcomes

Hypo-glycemia

Weight RelativeA1C Lowering when added to metformin

Other therapeutic considerations Cost

GLP-1R agonists lira: Superiorityin T2DM with clinical CVD

exenatide LAR &lixi: Neutral

Rare to GI side-effects, Gallstone diseaseContraindicated with personal / family history of medullary thyroid cancer or MEN 2Requires subcutaneous injection

$$$$

SGLT2 inhibitors Cana & empa:Superiority in

T2DM patientswith clinical CVD

Rare to Genital infections, UTI, hypotension, dose-related changes in LDL-C. Caution with renal dysfunction, loop diuretics, in the elderly. Dapagliflozin not to be used if bladder cancer. Rare diabetic ketoacidosis (may occur with no hyperglycemia). Increased risk of fractures and amputations with canagliflozin. Reduced progression of nephropathy & CHF hospitalizations with empagliflozin and canagliflozin in those with clinical CVD

$$$

DPP-4 Inhibitors alo, saxa, sita: Neutral

Rare Neutral Caution with saxagliptin in heart failureRare joint pain

$$$

Insulin glar: Neutraldegludec:

noninferior to glar

Yes No dose ceiling, flexible regimensRequires subcutaneous injection

$-$$$$

Thiazolidinediones Neutral Rare CHF, edema, fractures, rare bladder cancer (pioglitazone), cardiovascular controversy (rosiglitazone), 6-12 weeks for maximal effect

$$

-glucosidase inhibitor (acarbose)

Rare Neutral GI side-effects commonRequires 3 times daily dosing

$$

Insulin secretagogue:Meglitinide

Sulfonylurea

Yes

Yes

More rapid BG-lowering responseReduced postprandial glycemia with meglitinides but usually requires 3 to 4 times daily dosing.Gliclazide and glimepiride associated with less hypoglycemia than glyburide. Poor durability

$$

$

Weight loss agent (orlistat)

None GI side effectsRequires 3 times daily dosing

$$$

2018

UKPDS-34, obese sub-group (n=753)

◦ Newly diagnosed DM2, mean age = 53 y

◦ Duration of Rx ~10 yr, compared to conventional Rx

*

Any diabetes-related

endpoint

21%

*

Diabetes-related death

30%

**

All-cause

mortality

27%

†

Stroke

20%

**

Myocardialinfarction

33%

*p<0.01**p<0.005

†p=NS

NNT=15

UKPDS-34 Lancet 1998; 352: 854-65.Holman RR et al. N Engl J Med. 2008;359:1577-89.

10 yr follow-up:

ARR 8% 5% 7% 6% -

Incretin-based agents

◦ DPP-4 inhibitors

◦ GLP-1 receptor agonists

SGLT-2 inhibitors

Newer insulins

Incretin-based agents

◦ DPP-4 inhibitors

◦ GLP-1 receptor agonists

SGLT-2 inhibitors

Newer insulins

Baggio LL, Drucker DJ. Gastroenterology. 2007;132(6):2131-2157.

Insulin secretion

Glucagon secretion

Hepatic glucose

production Insulin secretion

Glucagon secretion

Hepatic glucose production

GLP

-1 r

ecep

tor-d

ep

en

den

t acti

on

s

Progressive GLP-1 activity

Satiety

Energy intake

Gastric emptying

Baggio LL, Drucker DJ. Gastroenterology. 2007;132(6):2131-2157.

Inhibit dipeptidyl peptidase 4 enzyme

GLP-1 inactive

metabolites

DPP-4

GLP-1

Agent Dose Frequency

sitagliptin (Januvia®) 100 mg

50 mg (eGFR 30-50)

Once daily

saxagliptin (Onglyza®) 5 mg

2.5 mg (eGFR 30-50)

Once daily

linagliptin (Trajenta®) 5 mg Once daily

15Linagliptin

Sitagliptin 5030 50 mg25 mg

Saxagliptin 5015 2.5 mg

eGFR (mL/min/1.73 m2): <15 15–29 30–59 60–89 ≥ 90CKD Stage: 5 4 3 2 1

CKD=chronic kidney disease.Sitagliptin Product Monograph, Merck, 2017; saxagliptin Product Monograph, AstraZeneca Canada, 2014; linagliptin product monograph, Boehringer-Ingelheim Canada, 2015.

Decision characteristic Response

After metformin?

A1c 7-8%

With coverage

Pill vs. injection? Pill

Side effectsVirtually non-existent;

No hypoglycemia

Weight Neutral

once daily

◦ liraglutide (Victoza ®)

◦ exenatide (Byetta ®)

once weekly

◦ dulaglutide (Trulicity ®)

◦ exenatide once-weekly (Bydureon ®)

◦ semaglutide (Ozempic ®)

◦ albiglutide**Albiglutide not available in Canada as of April 2018

Mean difference in A1C from baseline

Baseline A1C

8.2%

8.3%

8.2%

8.3%

8.4%

8.4%

Mean difference in weight from baseline

1. Exenatide Product Monograph, AstraZeneca Canada, 2014; 2. DeFronzo R et al. Diabetes Care 2005;28(5):1092-100; 3. Liraglutide Product Monograph, Novo Nordisk Canada, 2014; 4. Nauck M et al. Diabetes Care 2009;32:84-90; 5. Pratley R et al. Lancet 2010;375:1447-56; 6. Pratley R et al. Int J Clin Pract. 2011;65(4):397-407.

5μgexenatide:

-0.5%10μg

exenatide:

-0.9%

p≤0.05 p≤0.0001

vs. placebo (0.0%)

vs. placebo (-0.2 kg)

vs. placebo (-1.2 kg)

vs. sitagliptin (-0.96 kg)

1.2 mg liraglutide

-1.0% to

-1.2%

P<0.0001

1.8 mg liraglutide

-1.0% to

-1.5%

vs. placebo (+0.1%)

vs. sitagliptin (-0.9%)

Exenatide1,2

(5 µg BID)

Exenatide1,2

(10 µg BID)

Placebo

Liraglutide3-6

(1.2 mg QD)

Liraglutide3-6

(1.8 mg QD)

Placebo

-1.3 kg to

-2.6 kg

-2.6 kg to

-3.7 kg

Hypoglycemia risk is elevated when combined with a

sulfonylurea

SU=sulfonylurea; MET=Metformin; EXE=exenatide; LIRA=liraglutide; PBO=placebo; GLAR=glargine. Liraglutide Product Monograph, Novo Nordisk Canada, 2014; Exenatide Product Monograph, AstraZeneca Canada, 2014.

Exenatide 5 μg BID

Exenatide 10 μg BID

Liraglutide 1.2 mg QD

Liraglutide 1.8 mg QD

Placebo

Proportion of patients with hypoglycemia on incretin therapies in combination with metformin (± sulfonylurea)

5.3

12.6

2.5

16.7

4.5

19.2

0.8

27.4

5.3

27.8

2.5

28.9

16.9

0

10

20

30

40

50

60

70

80

90

100

+ MET + MET + SU

Sulfonylurea

+ MET + MET + SU

Glargine

EXEN 5µg

EXEN 10µg

PBO EXEN 5µg

EXEN 10µg

PBO LIRA1.8mg

PBOLIRA1.2mg

LIRA1.8mg

GLARPBOSU

Pro

po

rti

on

of

pati

en

ts (

%)

Doses: 0.75 mg, 1.5 mg; convenient s.c. injection device

Modified from: Dungan K et al. Lancet 2014. 384: 1349-57.

A1c

lowering

A1c

lowering

Dose: 2 mg/pen

No titration, one pen per week

Modified from: Buse JB et al. Lancet 2013. 381:117-24.

SUSTAIN-2◦ vs. DPP-4 inhibitor

SUSTAIN-3◦ vs. exenatide QW

SUSTAIN-4◦ vs. insulin - 2nd line

SUSTAIN-5◦ vs. basal insulin

SUSTAIN-6◦ CV outcomes trial**

SUSTAIN-7◦ vs. dulaglutide

SUSTAIN trials program

Doses: 0.25 mg, 0.5 mg, 1 mg

Sorli C et al. Lancet Diabetes Endocrin 2017; 5(4):251-60.

1.5%

eGFR (mL/min/1.73 m2): <15 15–29 30–59 60–89 ≥ 90CKD Stage: 5 4 3 2 1

Liraglutide* 50

Albiglutide 50

30

Dulaglutide 50

Exenatide (BID/QW) 30 50

* May be acceptable

to continue use

down to eGFR 30-45

based on studies

(LIRA-RENAL,

LEADER)

Davies MJ et al. Diabetes Care 2016; 39:222-30.Marso SP et al. N Engl J Med 2016; 375:311-22.

BID=twice daily; QW=once weekly.Liraglutide Product Monograph, Novo Nordisk Canada, 2017; Exenatide Product Monograph, AstraZeneca Canada, 2014; Dulaglutide product monograph, Lilly Canada, 2016.

Possible side effects Counselling

Nausea and/or vomiting• Transient• Resolves over time in most cases

Local site reaction • Minor, rarely requires discontinuation

Pancreatitis• Current data do not support a causal association but still considered an ongoing rare complication/risk

Gallstone disease• In susceptible individuals, based on LEADER trial results (3.1% vs. 1.9%)

Risk of medullary thyroid cancer (rat studies)

• No evidence to support any increased risk of medullary thyroid cancer development in humans• Avoid if personal or family history of

MTC or MEN2

Liraglutide product monograph, Novo-Nordisk Canada, 2017; Marso SP et al. N Engl J Med 2016; 375:311-22.

MET=metformin. Ahmann A et al. American Diabetes Association 2014. Abst 331-OR.Morrow L et al. Diab Obes Metab 2010; 13:75-80.

Baseline body weight: 90.2 kg 91.8 kg

Change in body weight: -3.54 kg -0.42 kg

Baseline: 8.3%

Insulin detemir/glargine +

liraglutide 1.8 mg (±MET)

n=226

ETD 95% CI: -1.19 [-1.39; -0.99]; p<0.0001

Baseline: 8.3%

Insulin detemir/glargine +

placebo (±MET)

n=225

Change in A1C from baseline at week 26

ETD 95% CI: -3.11 [-3.85 ; -2.37]; p<0.0001

-1.30%

-0.11%

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

Ch

an

ge in

A1

C f

ro

m b

aselin

e (

%)

>50% achieved

target with

liraglutide

add-on therapy

(vs. 14% placebo)

liraglutide 0.6 mg

s.c. daily x 1 week,

then 1.2 mg daily;

up to 1.8 mg od

Baseline Insulin

A1c change

>8.5% No ↓

7-8% ↓ 10%

<7.0% ↓ 20%

Decision characteristic Response

After metformin?

A1c 7-10%

With coverage

Pill vs. injection? Injection

Side effectsNausea/GI

No hypoglycemia

Weight Loss

Incretin-based agents

◦ DPP-4 inhibitors

◦ GLP-1 receptor agonists

SGLT-2 inhibitors

Newer insulins

↑ glucosuria

↑ natriuresis

SGLT-2=Sodium glucose co-transporter type 2

Matthaei S et al. Diabetes Care 2015; 38: 365-72.

Safety data available

for SGLT-2 inhibitors

out 3-4 years without

any unexpected AEs

Possible side effects Counselling

Urinary tract and genital mycotic (yeast) infections

• UTI 5.9 - 9.6% (women; mostly 1x)• Genital mycotic infections

Women 8.4 – 11.4%Men 4.2 – 5.4%

Volume depletion/hypotension• Patients should maintain adequate hydration; caution re: polypharmacy

Acute kidney injury• Hold medication during acute illness or dehydration (sick day management)

Diabetic ketoacidosis (DKA)• Reported cases observed in T2DM• Likely due to patient/insulin factors

eGFR (mL/min/1.73 m2): <15 15–29 30–59 60–89 ≥ 90CKD Stage: 5 4 3 2 1

Dapagliflozin 60

Empagliflozin 45

Canagliflozin 25 60*100 mg45

60*

• Reduced glycosuric effect at

lower eGFR (less effective!)

• May be renoprotective!!

(stay tuned…)

* = do not initiate if eGFR <60 ml/min

2016

CKD=chronic kidney disease.eGFR=estimated glomerular filtration rate.canagliflozin Product Monograph, Janssen Canada, 2015; dapagliflozin Product Monograph, AstraZeneca Canada, 2016; empagliflozin product monograph, Boehringer-Ingelheim Canada, 2016.

Decision characteristic Response

After metformin?

A1c 7-10%

With coverage

Pill vs. injection? Pill

Side effectsRisk of UTI/yeast infxn

No hypoglycemia

Weight Loss

DPP-4 INHIBITOR Date of Completion

sitagliptinTECOS Study:Trial Evaluating Cardiovascular Outcomes with Sitagliptin

CompletedNo differences in CV

outcomes

saxagliptinSAVOR-TIMI 53 Study:Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction 53

CompletedNo differences in CV

outcomes; possible increasein heart failure

linagliptinCARMELINA Study:Cardiovascular and Renal Microvascular OutcomE Study with LINAgliptin in Patients with Type 2 Diabetes Mellitus

January 2018Expected soon

alogliptin

EXAMINE Study:EXamination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome

CompletedNo differences in CV

outcomes

GLP-1 RECEPTOR AGONISTS Date of Completion

Dulaglutide

REWIND Study:The Effect of Dulaglutide on Major Cardiovascular Events in Patients with Type 2 Diabetes: Researching Cardiovascular Events with a Weekly INcretin in Diabetes

April 2019

Exenatide

EXSCEL Study:Exenatide Study of Cardiovascular Event Lowering Trial A Trial To Evaluate Cardiovascular Outcomes After Treatment With ExenatideOnce Weekly In Patients With Type 2 Diabetes Mellitus

CompletedNo differences in CV

outcomes

LiraglutideLEADER Study:Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results - A Long Term Evaluation

CompletedSuperiority over placebo in

patients with CVD

Lixisenatide*

ELIXA Study:Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With Lixisenatide

CompletedNo differences in CV

outcomes

*Lixisenatide is not approved in Canada as of March 2018

SGLT-2 INHIBITORS Date of Completion

EmpagliflozinEMPA-REG OUTCOME Study:Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes

CompletedSuperiority over placebo in

patients with CVD

DapagliflozinDECLARE TIMI-58 Study:Dapagliflozin Effect on CardiovascuLAR Events

April 2019

CanagliflozinCANVAS Study:CANagliflozin cardioVascular Assessment Study

CompletedSuperiority over placebo in patients with CVD; possible

increase in amputations, fractures

7,028 DM2 patients with established CVD

A1c 7 – 10%

Randomized to either empagliflozin 10 mg, 25 mg, or placebo

Mean follow-up 3.1 yrs

Originally non-inferiority design hierarchical progression to superiority

Pooled empagliflozin vs. placebo for results

Zinman B et al. N Engl J Med. 2015

Zinman B et al. N Engl J Med. 2015

Months

Pati

ents

wit

hevent

(%)

HR 0.86 95.02% CI (0.74, 0.99)

P < 0.001 for non-inferiorityp=0.04 for superiority

Placebo

Empagliflozin

No. of patients

Empagliflozin 4687 4580 4455 4328 3851 2821 2359 1534 370

Placebo 2333 2256 2194 2112 1875 1380 1161 741 166

PBO EMPA HR P NNT3

CV death, MI, stroke (%) 12.1 10.5 0.86 0.04 63

CV death (%) 5.9 3.7 0.62 <0.001 46

Nonfatal MI (%) 5.2 4.5 0.87 0.22

Nonfatal stroke (%) 2.6 3.2 1.24 0.16

Hosp. heart failure (%) 4.1 2.7 0.65 0.002 72

All-cause mortality (%) 8.3 5.7 0.68 <0.001 39

Based on recent evidence:

◦ Established cardiovascular disease

◦ Not at target A1c

◦ Using an agent with “demonstrated CV benefit”

Effect across all SGLT-2 inhibitors likely exists◦ CANVAS, DECLARE

2016

No. of patients

Canagliflozin 5795 5566 4343 2555 2460 2363 1661

Placebo 4347 4153 2942 1240 1187 1120 789

HR 0.86 95% CI (0.75, 0.97)

P < 0.001 for non-inferiorityp=0.02 for superiority

Outcome (per 1000 pt-y)

PBO CANA HR P or 95% CI NNT3

CV death, MI, stroke 31.5 26.9 0.86 0.02 44

CV deaths 12.8 11.6 0.87 (0.72-1.06)

Nonfatal MI 11.6 9.7 0.85 (0.69-1.05)

Nonfatal stroke 8.4 7.1 0.90 (0.71-1.15)

Hosp. heart failure 8.7 5.5 0.67 (0.52-0.87) 63

All-cause mortality 19.5 17.3 0.87 (0.74-1.01)

Canagliflozin reduced CV eventsPrimary outcome: CV death, non-fatal MI, or non-fatal stroke

Canagliflozin

Placebo

Neal B et al. N Engl J Med 2017

9,340 DM2 patients with established CVD or CKD, or age>60 with high-risk CV factors (MAlb, LVH, low EF)

A1c>7%

Randomized to either liraglutide up to 1.8 mg or placebo

Mean follow-up 3.8 yrs

Originally non-inferiority design hierarchical progression to superiority

Subgroup analysis for results in high-risk pts

Marso SP et al. N Engl J Med 2016;375(4):311-22.

Patients at risk

Liraglutide 4668 4593 4496 4400 4280 4172 4072 3982 1562 424

Placebo 4672 4588 4473 4352 4237 4123 4010 3914 1543 407

Marso SP et al. N Engl J Med 2016;375(4):311-22.

Time from randomization (months)

Pati

ents

wit

hevent

(%)

HR 0.87 95% CI (0.78, 0.97)

P < 0.001 for non-inferiorityp=0.01 for superiority

Placebo

Liraglutide

PBO LIRA HR P NNT4

CV death, MI, stroke (%) 14.9 13.0 0.87 0.01 53

CV death (%) 6.0 4.7 0.78 0.007 77

Nonfatal MI (%) 6.8 6.0 0.88 0.11

Nonfatal stroke (%) 3.8 3.4 0.89 0.30

Hosp. heart failure (%) 5.3 4.7 0.87 0.14

All-cause mortality (%) 9.6 8.2 0.85 0.02 72

Liraglutide reduced CV eventsCV death, non-fatal MI, or non-fatal stroke

Marso SP et al. N Engl J Med 2016;375(4):311-22.

Subgroup analyses

Recommendation 7

7. In adults with type 2 diabetes with clinical CVD in

whom glycemic targets are not achieved with existing

antihyperglycemic medication(s) and with eGFR >30

mL/min/1.73m2, an antihyperglycemic agent with

demonstrated CV outcome benefit should be

added to reduce the risk of:

a) major CV events [Grade A, Level 1A for empagliflozin; Grade

A, Level 1A for liraglutide; Grade C, Level 2 for canagliflozin]

b) heart failure hospitalization [Grade B, Level 2 for

empagliflozin; Grade C, Level 2 for canagliflozin],

c) progression of nephropathy [Grade B, Level 2 for

empagliflozin; Grade C, Level 3 for canagliflozin]

2018

CV, cardiovascular; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate

Recommendation 8

8. In adults with type 2 diabetes without clinical CVD in

whom glycemic targets are not achieved with existing

antihyperglycemic medication(s), incretin agents (DPP-

4 inhibitors or GLP-1 receptor agonists) and/or

SGLT2 inhibitors should be considered as add-on

medication over insulin secretagogues, insulin and

TZDs to improve glycemic control, if lower risk of

hypoglycemia and/or weight gain are priorities

[Grade A, Level 1A]

2018

HOLD the following medications:

Decision characteristic

DPP-4 inhibitor GLP-1 RASGLT-2inhibitor

After metformin?

A1c 7-8% 7-10%* 7-10%*

A1c reduction 0.5-1% 1-1.5% ~1%

With coverage

Pill vs. injection? Pill Injection Pill

Side effects None Nausea/GIRisk of UTI/

yeast infection

Hypoglycemia No No No

Weight Neutral Loss Loss

*esp. if prior clinical CVD

Incretin-based agents

◦ DPP-4 inhibitors

◦ GLP-1 receptor agonists

SGLT-2 inhibitors

Newer insulins◦ glargine-300 (Toujeo®)

◦ degludec (Tresiba®)

◦ Faster-acting aspart (Fiasp®)

3X concentrated

altered PK/PD profile

Less hypoglycemia

Smaller injection depots

Becker RHA et al. Diabetes Care 2015;38:637-643

Polymeric chain

Less hypoglycemia

Longer duration of action

~est. at 40 hours

Very flat profile

1. Owens DR, et al. Diabetes Metab Res Rev. 2014;30:104–19

2. Shah VN, et al. Diabetes Technol & Ther. 2013;15:727–32

3. Heise T , et al. Diabetes Obes Metab 2012;14:944–50

Upon

subcutaneous injection

forms soluble and

stable multihexamers,

that allow slow and

continuous absorption

of monomers into

the circulation1,2

0 4 8 12 16 20 24

0.8 U/kg

0.6 U/kg

0.4 U/kg

5

4

3

2

0

1G

luco

se

In

fusio

n R

ate

in

T1

DM

pa

tie

nts

at

Da

y 6

, m

g/k

g/m

in

Hours

▪ A half-life of ~25 hours, and is detectable

in serum for >120 hours post-injection2

degludec was noninferior to glargine with respect to

cardiovascular events; less hypoglycemia (DEVOTE)

“faster” NovoRapid Faster onset ~6 min

Shorter duration of action

Fiasp product monograph, Novo-Nordisk Canada, 2017;

Heise T et al. Diabetes, Obesity and Metabolism 2015; 17:682–688.

ThrLys

ThrTyr Phe Phe

GlyArg

Glu

Gly

Cys

Val

Leu

Tyr

Leu

Ala

Glu

Val

Leu

His

Ser

Gly

CysLeuHisGlnAsnValPhe

Gly

Ile

Val

Glu

GlnCys Thr Ser Ile Cys

Ser

Leu

Tyr

Gln

Leu

Glu

Asn

TyrCysAsn

Cys

B30

B28

A21

A1

B1

Asp

Nicotinamide

O

NH2

N

L-arginine

NH

H2N

NH

NH2

O

OH

• Inject up to 2 minutes before the meal OR

up to 20 minutes after starting the meal

IAsp

Faster aspart

Basal insulin/GLP-1 RA fixed-ratio combination therapies

Insulin glargine 100 U/mL+

Lixisenatide

Insulin degludec+

Liraglutide

IDegLiraiGlarLixi

*iGlarLixi and IDegLira not available in Canada as of April 2018

58 year-old man, tour operator

DM2 x 8 yr, MI age 54

A1c 8.7%

On metformin 1 g bid, gliclazide MR 120 mg daily, ramipril 5 mg daily, rosuvastatin 5 mg daily

Private drug coverage

BMI 34.3, BP 128/78, LDL 1.9

What would you recommend for him?

Early glycemic control in DM2 by prompt intensive intervention reduces the risk of complications

An expanded “tool-kit” presents greater therapeutic choices to achieve glycemic target in patients with type 2 diabetes

Rigorous CV outcomes trials demonstrate the benefit of newer diabetes agents towards reducing cardiovascular events in pts with prior clinical CVD

Email: ferhan.siddiqi@nshealth.ca