Development Committee CHAIR PowerPoint Presentation

Development Committee

CHAIR

Lawrence A. Leiter, Endocrinology & Metabolism, University of Toronto, Toronto

STEERING COMMITTEE

Harpreet S. Bajaj, Endocrinology & Metabolism, LMC Diabetes & Endocrinology, Brampton 

C. Keith Bowering,

Diabetologist

, Internal

Medicine, University of Alberta, Edmonton 

Alice Y. Y. Cheng, Endocrinology & Metabolism, University of Toronto, Toronto

Jean-Marie

Ekoé

, Endocrinology & Metabolism, Université de Montréal, Montreal 

Pierre

Filteau

, General Practice, Saint-Marc-Des-

Carrières

Stewart B. Harris, Family Medicine, Epidemiology & Biostatistics, Western University, London 

Ronald M. Goldenberg, Endocrinology & Metabolism, LMC Diabetes & Endocrinology, Thornhill 

Vincent C. Woo, Endocrinology & Metabolism, University of Manitoba, Winnipeg 

Jean-François Yale, Endocrinology & Metabolism, McGill University, Montreal 

EDUCATIONAL COMMITTEE

Carl Fournier, Family Physician, Montreal 

Theodore J. Jablonski, Family Physician, Calgary 

Kevin K. Saunders, Family Physician, Winnipeg 

Richard Ward, Family Physician, Calgary

Faculty/Presenter Disclosure

Faculty:

[Speaker

’

s name]

Relationships with commercial interests:

Grants / research support:

Speakers Bureau / honoraria:

Consulting fees:

Other:

Disclosure of Commercial

Support

This program has received financial support from Merck Canada Inc. in the form of an educational grant.

This program has received in-kind support from Merck Canada Inc. in the form of logistical support.

Potential for conflict(s) of interest

:

[Speaker name]

has received

[payment/funding, etc.]

from Merck Canada Inc.

Merck Canada Inc. benefits from the sale of the products that will be discussed in this program: Sitagliptin (Januvia

®

), Combination Sitagliptin/Metformin (Janumet

®

).

Mitigating Potential Bias

The information presented in this CME program is based on recent information that is explicitly

“

evidence-based.

”

This CME Program and its material is peer-reviewed and all the recommendations involving clinical medicine are based on evidence that is accepted within the profession. All scientific research referred to, reported or used in the CME/CPD activity in support or justification of patient care recommendations conforms to the generally accepted standards.

Objectives

Following this program,

participants will be able to:

Identify glycemic targets for patients with T2DM

Appropriately select a third antihyperglycemic agent (AHA) for patients with inadequate glycemic control on metformin + sulfonylurea (SU)

Identify strategies to improve adherence in patients on polypharmacy

Recognize and manage side effects associated with the different AHAs

55-year-old male full-time teacher

T2DM duration: 8 years with no known complications

BMI: 32 kg/m

2

(gained 4 kg over last year)

BP: 135/85 mmHg

HR: 84 bpm

Sedentary lifestyle

Is unhappy

“

taking all these pills”

MedicationsMetformin 1,000 mg BIDSU prescribed as BID StatinACEiASAPPIAntidepressant

LabsA1C 7.9% FPG 8.4 mmol/LeGFR 75 mL/min/1.73m2ACR normalLipids at target

Case 1

Case 1

What would the target A1C be for this patient?

Individualizing A1C Targets

Consider 7.1-8.5% if:

Most patients

with type 1

and type 2

diabetes

A target ≤ 6.5% may be considered in some patients with type 2 diabetes to further lower the risk of nephropathy and retinopathy which must be balanced against the risk of hypoglycemia

Limited life expectancy

High level of functional dependency

Extensive coronary artery disease at high risk of ischemic events

Multiple co-morbidities

History of recurrent severe hypoglycemia

Hypoglycemia unawareness

Longstanding diabetes patient for whom it is difficult to achieve an A1C ≤ 7%, despite effective doses of multiple antihyperglycemic agents, including intensified basal-bolus insulin therapy

7%

≤7%

>7%

Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2013;37:S31-34.

Case 1

Before adding another antihyperglycemic agent, what other interventions could you consider?

Case 1 (continued)

Upon questioning, the patient reveals that he works late and sometimes forgets his evening dose of metformin and SU. A pharmacist, who is also a diabetes educator, reviews his diet and provides compliance packaging of his medications. A kinesiologist working in your team suggests an

“

exercise prescription.

”

He returns in 3 months and his A1C has improved to 7.4%.

Case 1

Would you add a third antihyperglycemic agent? If so, what would you add?

Start metformin immediately

Consider initial combination with another

antihyperglycemic

agent

Start lifestyle intervention (nutrition therapy and physical activity) +/- metformin

A1C < 8.5%

Symptomatic hyperglycemia with metabolic decompensation

A1C

 8.5%

Initiate insulin +/-

metformin

If not at glycemic target (2-3 mos)

Start / increase metformin

If not at glycemic targets

L

I

F

E

S

T

Y

L

E

See next page

AT DIAGNOSIS OF TYPE 2 DIABETES

Canadian Diabetes Association Clinical Practice Guidelines Expert Committee.

Pharmacologic Management of Type 2 Diabetes: 2016 Interim

Update.

Can J Diabetes. 2016;40:193-195.

Add another agent best suited to the individual by prioritizing patient characteristics:

PATIENT CHARACTERISTICS

CHOICE OF AGENT

Priority:

Clinical Cardiovascular Disease

Antihyperglycemic agent with demonstrated CV outcome benefit (

empagliflozin

, liraglutide)

• Degree of hyperglycemia

• Risk of hypoglycemia

• Overweight or obesity

• Cardiovascular disease or multiple risk factors

• Comorbidities (renal, CHF, hepatic)

• Preferences & access to treatment

• Consider relative A1C lowering

• Rare hypoglycemia

• Weight loss or weight neutral

• Effect on cardiovascular outcome

• See therapeutic considerations, consider eGFR

• See cost column; consider access

If not at glycemic target



Add

another agent from a different

class



Add/intensify insulin regimen

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

Canadian Diabetes Association Clinical Practice Guidelines Expert Committee.

Pharmacologic Management of Type 2 Diabetes: 2016 Interim Update.

Can J Diabetes.

2016;40:193-195.

LIFESTY

LE

Add another class of agent best suited to the individual

(classes listed in alphabetical order):

Class

Relative A1C

Lowering

Hypo-

glycemia

Weight

Effect in Cardiovascular Outcome Trial

Other Therapeutic considerations

Cost

Alpha-glucosidase

inhibitor (

acarbose

)



Rare

Neutral to



Improved postprandial control,

GI side-effects

$$

DPP-4 inhibitors



Rare

Neutral to



Alo

,

saxa

,

sita

: neutral

Caution with saxagliptin in heart failure

$$$

GLP-1R agonists

 to 

Rare



Lira: superiority in T2DM patients with clinical CVD

Lixi

: neutral

GI side effects

$$$$

Insulin



Yes



Glar

: neutral

No dose ceiling, flexible regimens

$-$$$$

Insulin

secretagogue

:

Meglitinide

Sulfonylurea





Yes

Yes





Less

hypoglycemia in context of missed meals but usually requires TID to QID

dosing

Gliclazide

and glimepiride associated with less hypoglycemia than glyburide

$$

$

SGLT2 inhibitors

 to 

Rare



Empa

: superiority in T2DM patients with clinical CVD

Genital infections, UTI,

hypotension, dose-related changes in LDL-C, caution with renal dysfunction and loop diuretics, dapagliflozin not to be used if bladder cancer, rare diabetic ketoacidosis (may occur with no hyperglycemia)

$$$

Thiazolidinediones



Rare



Neutral

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

$$

Weight loss agent (orlistat)



None



GI side effects

$$$

alo

=alogliptin;

empa-empagiflozin

;

glar

-glargine;

lixi-lixisenatide

;

saxa

-saxagliptin;

sita

-sitagliptin

Case 1

Discuss the advantages and disadvantages of the various options for adjusting antihyperglycemic agents in this case.

Adapted from Han S

et al

. Curr Med Res Opin. 2012;28(6):969-77.

CDT = coadministered dual therapy; FDC = fixed-dosed combination

Study

Blonde L

et al

, 2003

Thayer S

et al

, 2010

Thayer S

et al

, 2010

Duckworth W

et al

, 2003

Raptis AE et al

, 1990

Overall

Mean difference

of A1C

(95% CI)

Weight (%)

Baseline A1C

-0.53% (-0.80, -0.26)

28.0%

9.1–9.2%

-0.31% (-0.66, -0.04)

22.7%

8.0–8.1%

-0.45% (-0.77, -0.13)

24.7%

7.3–7.8%

-0.60% (-0.97, -0.23)

21.4%

8.3%

-2.30% (-3.65, -1.00)

3.2%

10.6%

-0.53% (-0.78, -0.28)

100%

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

Mean difference in HbA1C (FDC – CDT)

Favours FDC

Fixed-dose Combination Therapy is Associated with Improved Glycemic Control

Lozano-Ortega

G, et al. Network meta-analysis of treatments for type 2 diabetes mellitus following failure with metformin plus sulfonylurea. Curr Med Res Opin. 2016 May;32(5):807-16

.

* Significant vs. PBO; NS= not significant vs placebo

Network Meta-analysis Comparing

Antihyperglycemic

Drugs as

Add-ons to

Metformin

Plus SU

Change in

A1C vs. PBO

(%)

Change in

wt vs. PBO

(kg)

Change in SBP vs. PBO

(mm Hg)

Risk of hypoglycemia vs. PBO (OR)

DPP-4 inhibitors

-0.68*

NS

NS

2.99*

GLP-1R agonists

-1.07*

-1.14*

NS

3.26*

SGLT2 inhibitors

-0.86*

-1.71*

-3.73*

3.12*

TZDs

-0.93*

+3.62*

NS

2.64*

Insulin: basal

-1.08*

+2.63*

NS

5.61*

Insulin: premixed

-1.30*

+3.98*

NS

11.62*

Insulin: bolus

-1.54*

+5.69*

NS

38.90*

0.0

-0.2

-0.4

-0.6

-0.8

-1.0

-1.2

-1.4

* Significant vs. comparator

Change in A1C from baseline (%)

Wilding J, et al.

Int J Clin Pract

2013;67:1267–82.

Wilding J, et al. ADA 2012. Abstract 1022-P.

Matthaei

S, et al.

Diabetes Care

2015;

38:365–72.

Haring HU, et al.

Diabetes Care

2013;36:3396–404.

MET + SU combination

24 weeks

BL A1C

~

8.1%

-0.82*

0.2

0.4

Canagliflozin (CANA)

EMPA 10 OD

PBO

MET + SU combination

26 weeks

BL A1C

~

8.1%

-0.85*

-0.13

CANA 100 OD

PBO

Δ wt (kg):

Hypos (%):

MET + SU combination

24 weeks

BL A1C

~

8.2%

-0.86*

DAPA 10 OD

PBO

-0.17

-1.06*

-0.17

-0.77*

EMPA 25 OD

CANA 300 OD

Placebo-controlled Clinical Trials of

SGLT2 inhibitor as an Add-on to Metformin + SU

-2.1*

25.8

-2.6*

30.1

-0.7

15.4

Dapagliflozin (DAPA)

Empagliflozin (EMPA)

-2.7*

12.8*

-0.6

3.7

-2.2*

16.1

-2.4*

11.5

-0.4

8.4

SGLT2: sodium-glucose cotransporter 2; MET: metformin; SU: sulfonylurea; BL: baseline; A1C: glycated hemoglobin; PBO: placebo

Case 1

What side effects could the patient experience with the new therapy/therapies and how would you and the patient co-manage them?

DPP-4 INHIBITORS

MAJOR ADVERSE CV EVENTS & HEART FAILURE (HF)

Reassure

Alogliptin (EXAMINE), Saxagliptin (SAVOR) and Sitagliptin (TECOS) neutral on major adverse CV events

Alogliptin and sitagliptin neutral on HF

Saxagliptin increased HF (SAVOR), so use with caution in patients with

HF

FDA warning for

both

saxagliptin and

alogliptine with respect to risk of hospitalization for HFPANCREATIC ISSUES

ReassureMeta-analysis of SAVOR, EXAMINE and TECOS suggest a small increased risk of pancreatitis (1/1000-1/2000)Avoid if the patient has a history of pancreatitisACARBOSEGASTROINTESTINAL SIDE EFFECTSTitrate slowlyBuse JB, et al. Pancreatic safety of sitagliptin in the TECOS study. Diabetes Care. 2016 Sep 14. pii: dc152780. [Epub ahead of print]

GLP-1R AGONIST

GASTROINTESTINAL SIDE EFFECTS

Reduce metformin

Slowly titrate the dose

Decrease meal portions and reduce fat content

Provide hand-holding reassurance – inform patients

that GI issues are transient

ENDOCRINE ISSUES

Thyroid medullary cancer occurred in rodents

Not observed in monkeys and humans

No other related thyroid issues

Avoid if patient has a personal or family history of MTC or if patient has MEN2PANCREATIC ISSUES Reassure and discussEMA release and ADA/EASD/IDF position statement No signal of increased risk of pancreatitis in ELIXA and LEADER trialsNon-significant excess of pancreatic cancer vs. placebo in the LEADER trialAvoid if the patient has a history of pancreatitisMAJOR CV EVENTS & HEART FAILURE (HF) ELIXA reported neutral results for rates of MACE and HHF LEADER reported reduced risk for MACEMETFORMIN

GASTROINTESTINAL SIDE EFFECTSTake in the middle of the mealTry different brand/formulation of metformin or switch to a DPP-4 fixed-dose combinationSlowly down-titrate and continue to use if the patient is able to tolerate a lower doseLimit dose to 1,500 or 2,000 mg a dayAdd a second agent before up-titrating to the maximum dose

SGLT2 INHIBITORS

GENITAL MYCOTIC INFECTIONS (GMI)

Reassure

GMIs are infrequent, more common in women, usually mild to moderate and easily treated,

plus, most with GMI have only 1 event

Consider proactive prescription (cream or fluconazole)

Encourage local hygiene

Avoid if resistant GMIs recur

LIPID PROFILE

Small increase in LDL-C of about 0.1 to 0.2

mmol

/L on average – dose-dependent Reassure that HDL-C also goes up Empagliflozin superior for MACE and CV mortality in patients with established CVD in EMPA-REG OUTCOME Ongoing long-term trials will provide more informationPOLYURIA/POLLAKIURIA Occurs in 3-6% of patients Provide reassurance as polyuria/pollakiuria may be temporary Consider reducing diuretic dose or stopping entirely, as it may not be necessary Avoid alcohol and coffee

DIABETIC KETOACIDOSIS (DKA) Rare (≤0.1%), usually associated with major illness, dietary restriction (low carbohydrate or reduced intake), inappropriate insulin reduction. May be euglycemic Most cases are in insulin-treated patients, some of whom have had unrecognized T1D or LADAHYPOTENSION

Consider reducing the dose of the antihypertensive agent(s) (start with the diuretic if taking) if blood pressure is low-normal or volume-depleted

Down-titrate, as the occurrence of hypotension may be dose-dependent

If patient has concomitant diseases, stop temporarily (SADMANS)

MALIGNANCIES

10:1 imbalance in bladder cancer in dapagliflozin trials

Not observed with other SGLT2 inhibitors

Most of the cases of bladder cancer occurred in patients who had hematuria at baseline

Dapagliflozin should not be used in patients with a history of bladder cancer

URINARY TRACT INFECTIONS (UTI)

Reassure

20-30% higher rates than placebo in pooled analyses

More common in women, mild to moderate

Most with UTI have 1 event

FRACTURESRare fractures with canagliflozinHigher rates of fractures: may be in part related to more falls related to hypotensionReduction in bone mineral density: may be in part related to weight loss. Increased phosphate levels and PTH levels may also contributeNo increase in EMPA-REG OUTCOME trial

SULFONYLUREAS

HYPOGLYCEMIA

If possible, switch to an incretin agent or a SGLT2 inhibitor

Provide/refer for education on nutrition, physical activity, alcohol

If staying on sulfonylureas

Decrease dose

Use gliclazide or glimepiride in the morning

(discuss timing) rather than glyburide

Use repaglinide if skipping meals

Verify eGFR

Reduce dose or discontinue if patient becomes illWEIGHT GAIN

Lifestyle changesIf possible, switch toAcarboseDPP-4 inhibitorGLP-1R agonistSGLT2 inhibitorTo avoid hypoglycemiaUse gliclazide rather than glyburideUse repaglinide if skipping meals

THIAZOLIDINEDIONES (TZD)

MYOCARDIAL INFARCT CONCERNS

Not an issue with pioglitazone

Pioglitazone may reduce stroke and revascularization

Controversial

Not demonstrated by all meta-analyses

Not demonstrated in RCTs

HEART FAILURE

Use of rosiglitazone and pioglitazone has been associated with a >2-fold increased risk of heart failure

EDEMA

Switch to another class of AHA

Avoid if patient has a history of CHFAs edema is more evident with insulin, avoid combining TZDs with insulinInitiate potassium-sparing diureticsMALIGNANCIES (BLADDER CANCER)RareAlthough a signal has been suggested by some observational studies, an ADA position statement states there is no causal relationshipFDA has indicated that TZDs are safe except in those with a (family) history of bladder cancerNOT an issue with rosiglitazone

FRACTURESEvidence that TZDs double the risk of fractures after 3 years of usage (MOA is integral to this class effect)Switch to a different class of AHANote that BMD is not a predictor for fracturesWEIGHT GAINEncourage healthy lifestyle changesReduce doseAs weight gain is more evident with insulin, avoid combining TZDs with insulin

If possible, switch to acarbose, a DPP-4 inhibitor, a GLP-1R agonist, or a SGLT2 inhibitor

NEWER AGENTS + SU/INSULIN

HYPOGLYCEMIA

Consider reducing SU/insulin dose when adding

DPP-4 inhibitor, GLP-1R agonist or SGLT2 inhibitor

if the A1C is not very high

Recognize and educate on the variability in glucose levels

SU, INSULIN & DRIVING

HYPOGLYCEMIA

Consider switching to another class

The patient should be advised to:

Test glucose levels before driving and every 4 hours if s/he is on a long trip

Keep a meter and source of carbohydrate handyNOT drive if blood glucose is under 5.0 mmol/LPull over if experiencing symptoms of hypoglycemiaNOT drive for an hour even after an occurrence of mild hypoglycemia

Adapted

from: Product Monographs as of Nov.

2016;

Harper W et al. Can J Diabetes 2015;39:250-252.

<15

5

15-29

4

30-59

3

≥90

1

60-89

2

CKD Stage

eGFR

(mL/min/1.73m

2

)

25

Acarbose

30

60

Metformin

50

30

6.25 mg

12.5 mg

Alogliptin

15

Linagliptin

15

50

2.5 mg

Saxagliptin

50

30

25 mg

50 mg

Sitagliptin

30

50

Exenatide (BID/QW)

50

Albiglutide

50

Dulaglutide

30

50

Liraglutide

15

30

Gliclazide/glimepiride

30

50

Glyburide

Repaglinide

45

60*

Canagliflozin

60

Dapagliflozin

45

60*

Empagliflozin

30

Thiazolidinediones

Contraindicated

Not recommended

Caution and/or dose reduction

No dose adjustment but dose

monitoring of renal function

Safe

Do not initiate if

GFR

< 60 mL/min/1.73m

2

SGLT2

inhibitors

Insulin

secretagogues

GLP-1

receptor

agonists

DPP-4

inhibitors

Biguanide

ɑ-Glucosidase

inhibitor

Antihyperglycemic Agents and Renal Function

10 or 25 mg

100 mg

FEAR ABOUT INTENSIVE GLUCOSE CONTROL AND MORTALITY

Intensive control has been proven to reduce microvascular complications, particularly nephropathy

Guidelines suggest intensive therapy to achieve

- A1C

≤

6.5% when there is no risk of hypoglycemia to reduce microvascular complications

-

≤

7.0% in most patients

- 7.1% to 8.5% in people with short life expectancy, extensive CAD at high risk of ischemic events or recurrent severe hypoglycemia

• One study (ACCORD) showed an increase in CV and total mortality in patients randomized to intensive glycemic control, but this risk was confined to those not achieving A1C ≤ 7% and was not demonstrated in a meta-analysis

- Reduced myocardial infarctions – also demonstrated in a meta-analysis• Although there is a link between severe hypoglycemia and mortality, a causal relationship has not been provenKEY MESSAGESMedication side effects can affect adherence, quality of life and, ultimately, glycemic control Ask about side effects and make therapeutic choices to maximize tolerability

Conclusions

In most patients, strive for an A1C target of ≤7.0%

For patients who are not at target, first consider adherence and lifestyle modification prior to altering medical therapy

The choice of a

“

third agent

”

should be individualized to the patient

’

s characteristics,

co-morbidities and values

Back-up Slide

Options for Adjusting AHA Therapy

Pros

Cons

Keep sulfonylurea but change to once-a-day formulation, add a

DPP-4 inhibitor as a once-daily FDC

Only 4 pills a day (instead of current 6), all in the a.m. (versus twice a day currently)

Least change with current regimen

Keep sulfonylurea but change to once-a-day formulation, add an

SGLT2 inhibitor

Decrease in A1C, weight loss, reduction in BP, possible CV and renal long-term benefit

Higher cost, side effects of SGLT2 inhibitors (refer to table)

Stop sulfonylurea, replace with an SGLT2 inhibitor

Reduction of A1C (but may not reach target), weight loss, reduction in BP, possible CV and renal long-term benefit

Higher cost, side effects of SGLT2 (refer to figure)

Stop sulfonylurea, replace with a

GLP-1R agonist

Reduction of A1C, probably reaching goal, weight loss, reduction in BP

Injection, higher cost, side effects of GLP-1R (refer to figure)

Stop sulfonylurea, replace with an SGLT2 inhibitor + a GLP-1R agonist

Greatest reduction in A1C, greatest weight loss and BP reduction

Injection, highest cost, side effects of both classes added (refer to figure), off-label use.