the flozins quest for clarity? - dalhousie university · dalhousie university office of ... met ins...
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– http://www.medicine.dal.ca/departments/core-units/cpd/programs/academic-detailing-service.html
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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.
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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
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Sodium glucose co-transporter 2 inhibitors
• Canagliflozin (Invokana)
• Dapagliflozin (Forxiga)
• Empagliflozin (Jardiance)
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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
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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
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Annabel
Medications
• Irbesartan/HCTZ 150/12.5 daily
• Atorvastatin 40 mg daily
• Metformin 1000mg BID
• Gliclazide 160 mg daily
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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 ↓
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
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Annabel
Medications
• Irbesartan/HCTZ 150/12.5 daily
• Atorvastatin 40 mg daily
• Metformin 1000mg BID
• Gliclazide 160 mg daily
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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