The Flozins Quest for Clarity?

Choosing Wisely with Academic Detailing 2018

ARE THEY THE REAL DEAL

Disclosure statements

• The Academic Detailing Service is operated by Dalhousie Continuing Professional Development, Faculty of Medicine and funded by the DHW. Dalhousie University Office of Continuing Professional Development has full control over content.

– http://www.medicine.dal.ca/departments/core-units/cpd/programs/academic-detailing-service.html

2

Disclosure statements

• Isobel Fleming has no actual or potential conflict of interest in relation to this topic or presentation

• Dr. Brian Moses has presented CME presentations sponsored by Boehringer Ingelheim, Janssen and Astra Zeneca.

3

Learning Objectives

• To review the evidence evaluating sodium glucose co-transporter 2 inhibitors (SGLT2) in type 2 diabetes

• To discuss a patient case

• To promote clinical sharing and discussion about the appropriate place in therapy of the SGLT2 inhibitors

4

Sodium glucose co-transporter 2 inhibitors

• Canagliflozin (Invokana)

• Dapagliflozin (Forxiga)

• Empagliflozin (Jardiance)

5

Evidence from

• Canagliflozin (Invokana) CANVAS Trial

– N Engl J Med 2017;377: 644-57

• Empagliflozin (Jardiance) EMPA-REG OUTCOME Trial

• N Engl J Med 2015;373: 2117-28

• Liraglutide (Victoza) LEADER trial

• N Engl J Med 2016;375: 311-22

6

Annabel

• 70 year old active senior

• Past history

– Hypertension 15 years

– T2DM 12 years

• Lab work

– BP 132/78

– eGFR 58

– A1C 8.0

– LDL 2.0

7

Annabel

Medications

• Irbesartan/HCTZ 150/12.5 daily

• Atorvastatin 40 mg daily

• Metformin 1000mg BID

• Gliclazide 160 mg daily

8

Annabel

Would you add an SGLT2 inhibitor?

Would you make any other changes?

9

Insulin resistance

inefficient Insulin

secretion

T2DM

What is T2DM?

Age

↑Body fat

Environment

Genes

Complications

• ACUTE– Hypoglycemia

– HHNS

• CHRONIC– Microvascular

• Retinopathy

• Nephropathy

• Neuropathy

– Macrovascular

• Accelerated

atherosclerosis

• MI

• Stroke

• Lower extremity gangrene

– CHF

80%

Well designed RCTs wanted

2 TYPES

Target trials

Compare A1C levels

Drug trials

Compare A1C lowering therapies

Will a ↓A1C ↓vascular events?

Study Microvascular CVD Mortality

UKPDS ↓ ↓ ↔ ↓ ↔ ↓

ACCORD ↓ ↔ ↑

ADVANCE ↓ ↔ ↔

VADT ↔ ↔ ↔

Initial trial Long term F/U

Microvascular outcomes…

↓ early indicators

– Retinopathy

– Nephropathy

Macrovascular outcomes…. ????

Did you know…agents can be approved without direct evidence

that they ↓ risk of morbidity & mortality

Well designed RCTs wanted

2 TYPES

Target trials

Compare A1C levels

Drug trials

Compare A1C lowering therapies

How do the therapy options compare ? Exposes effects of mechanisms outside of AIC ↓?

Glucose lowering

agent

Outcomes

Retinopathy,

nephropathy,

neuropathy

CVD death, MI,

stroke

Mortality

SUs ??? ???

Repaglinide ??? ???

TZDs

Pioglitazone ↓ MACE?↑ risk HF ? ???

Rosiglitazone ↑ risk HF & MI ???

DPP-4 Inhibitors

Sita-, saxa- & alogliptin No benefit vs Pl No benefit vs Pl

linagliptin ??? ???

GLP agonists

Dulaglutide, Albiglutide ??? ???

Exenatide No benefit vs Pl No benefit vs Pl

Liraglutide ↓ MACE vs Pl ↓ risk vs PlSGLT-2 Inhibitors

Dapagliflozin ??? ???

Canagliflozin ↓ MACE ???

Empagliflozin ↓ MACE vs Pl ↓ risk vs PlInsulin ??? ???

Outcomes

SGLT2 GLP-1

EMPA REG

Empagliflozin

10mg or 25mg

CANVAS

Canagliflozin 100mg - 300mg (71%

300mg)

LEADER

Liraglutide

1.8 mg

Median f/u

yrs

3.1 2.4 3.8

CV death,

MI, stroke

10.5% vs 12.1%

0.86 (0.74-0.99)

ARR 1.6%

NNT 63

6.5% vs 7.6%

0.86 (0.75-0.97)

ARR 1.1%

NNT 90

13% vs 14.9%

0.87 (0.78-0.97)

ARR 1.9%

NNT 53

CV death 3.7 vs 5.9

0.62 (0.49 - 0.77)

ARR 2.2

NNT 45

NS ↓ (RR 0.87) 4.7% vs 6%

0.78 (0.66 - 0.93)

ARR 1.3%

NNT 77

Non-fatal MI NS ↓ (RR 0.87) NS ↓ (RR 0.85) NS ↓ (RR 0.88)

Stroke NS ↑ (RR 1.18) NS ↓ (RR 0.90) NS ↓ (RR 0.86)

Who do these results apply to?

EMPA REGn=7,020

3.1 yrs f/u

CANVASn=10,1422.4 yrs f/u

LEADERn=9,340

3.8 yrs f/u

Trial population

99.5% CVD

10% HF

65.6% CVD

14.4% HF

81% CVD

18% HF

Time since Diagnosis

≤ 5yr (18%)>5-10 (25%)>10 (57.4%)

13.5 yrs 12.8 yrs

% eGFR 30-60

26%Included but

% not reported21%

MACE /yr CV death/yr

4%1.8%

3.2%1.3%

4%1.6%

Vascular OutcomeStudies

% patients on background medications

Met Ins ASA/AP

Statin B block ACE/ARB

Diure-tics

SGLT2EMPA-REGempagliflozin 74 49 94 77 64 81 43

SGLT2CANVAScanagliflozin 77 50 74 75 54 80 44

GLP-1LEADERLiraglutide

77 44 92 73 56 83 42

What caused the results?

• Not A1C

• Pattern of CV benefit

– Different for empagliflozin and canagliflozin than with liraglutide

Change in

A1C

EMPA REG CANVAS LEADER

8 → 7.8vs 8.2

8.2 → 7.7vs 8.1

8.7 → 7.8vs 8.2

Outcomes

HR (95% CI)

SGLT2 GLP-1

EMPA REG

Empagliflozin

CANVAS

Canagliflozin

LEADER

Liraglutide

Hosp for

Heart

Failure

0.65

(0.50-0.85)

0.67

(0.52 – 0.87)

NS ↓

Other benefits

Both empagliflozin and canagliflozin

Best guess of underlying causefor SGLT2 inhibitors

Also:•Early hemodynamic changes, ↓ whole body Na+ content•↓ BP and weight•↓ cardiac O2 demand •Changes in cardiac energy metabolism

Adverse effects• Genital & UT infections

• Genital infections NNH 22 empagliflozin

• Genital infections NNH 6 (females), 12 (males) canagliflozin

• UTIs NNH 24 (females with empagliflozin)

• Volume depletion (dry mouth/polydipsia to orthostatic hypotension/syncope)

• NNH 14 to 38 (canagliflozin)

• Amputations • NNH 96 (canagliflozin)

• Fractures • NNH 286 (canagliflozin)

• Increase potassium, hemoglobin and hematocrit

Adverse effects

• Diabetic ketoacidosis

• Post marketing Health Canada warnings:– Acute kidney injury (canagliflozin and dapagliflozin) 2015

– Fractures and amputations with canagliflozin Sept 2017

Unanswered questions

• Are CV benefits a class effect?

• What about effects in

– people without established CVD

– new onset T2DM

– people without T2DM

• Will a combination of these agents show additive CV benefit?

Drug ~ $ per dayMetformin

GlucophageGlumetza

< 0.251.25 – 2.50

SecretagoguesDiabeta & DiamicronAmarylGlucoNorm (repaglinide)

< 0.250.50 – 1.000.50 – 3.00

Pioglitazone 0.60 – 1.25

DPP-4 inhibitors 2.85

SGLT-2 inhibitors 2.85

GLP-1 agonists 5.20 – 9.00

Annabel

• 70 year old active senior

• Past history

– Hypertension 15 years

– T2DM 12 years

• Lab work

– BP 132/78

– eGFR 58

– A1C 8.0

– LDL 2.0

28

Annabel

Medications

• Irbesartan/HCTZ 150/12.5 daily

• Atorvastatin 40 mg daily

• Metformin 1000mg BID

• Gliclazide 160 mg daily

29

Annabel

Would you add an SGLT2 inhibitor?

Would you make any other changes?

30

Annabel

If Annabel had experienced a recent TIA and was started on low dose ASA,

Would this influence your decision?

Canadian Diabetes Association 2018 Guidelines

For patients not at target after metformin,

consider adding

empagliflozin, canagliflozin or liraglutide

In

Patients with clinical CVD

Canadian Diabetes Association 2018 Guidelines

For patients not at target after metformin,

consider adding

An agent best suited to the individual

By

Prioritizing patient characteristics

Are SGLT2s the REAL DEAL for Annabel