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Journal Club; Jun 23, 2016 – Shermaine Ngo
Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes
Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck Ma, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. New
England Journal of Medicine. 2016 Jun 13.
Background  Liraglutide: GLP-1 receptor agonist

Rationale
Trial Design
Dosing: 0.6mg SC once daily – 1 week  1.2mg SC once daily – 1 week  1.8mg SC once daily
Current literature: No evidence on hard outcomes; previous trials mainly on weight loss, HbA1c, etc.
Current literature shows association with reductions in weight, blood pressure and lowering glucose levels.
∴ LEADER trial aims to assess the long term safety and effects of liraglutide on cardiovascular outcomes
"Concerns...about cardiovascular safety of anti-hyperglycemic therapies…regulatory authorities had mandated
cardiovascular safety assessment of new diabetes treatments"
Trial Design:
-
Multi-centred, international, randomised double-blind placebo-controlled trial
-
Objective
Patient
Population
Liraglutide 1.8mg SC once daily (or maximum tolerated dose) vs. placebo in addition to the care of subjects
that will otherwise be decided by the subject’s physician(s).
o Additional glucose-lowering medications may be added to achieve target glycemic control
o Exceptions: drugs affecting incretin pathway (GLP-1 RA, DPP-4 inhibitors), pramlinitide
Randomised in a 1:1 manner to receive a once daily dose of maximum 1.8 mg of liraglutide or equivalent
placebo as an add-on to their standard of care (SOC) treatment
o Blinded codes
o Interactive Voice/Web Response System
Duration: 18 months of recruitment period followed by 42 months (3.5 years) from last subject randomized
o Follow up: 42 to 60 months (of tx exposure) + 30 days post-treatment
Completed: when a minimum of 42 months after last subject randomised and number of primary endpoints
reported during the trial is equal to or greater than that assumed in the power calculation.
"Assess long-term efficacy and safety with regards to clinically important events or other surrogate parameters of
treatment for patients with T2DM that are at high risk for CV events"
1o Hypothesis: liraglutide would be non-inferior to placebo with regard to primary outcome
Setting:
Countries planned to participate: Austria, Belgium, Brazil, Canada, China, Czech Republic, Denmark, Finland, France,
Germany, Greece, Hungary, India, Ireland, Israel, Italy, Mexico, Netherlands, Norway, Poland, Romania, Russian
Federation, Serbia, South Africa, South Korea, Spain, Sweden, Taiwan, Turkey, UK, United Arab Emirate and US
Duration of Randomization: September 2010 through April 2012
For 90% Power to reject the null hypothesis that the hazard ratio is > 1.3:
Assume: 1. withdrawal rate < 10%, 2. annual primary event rate of 1.8% in each group, 3. min exposure of 42
months, 4. one-sided alpha-level of 0.025, 5. non-inferiority margin vs. placebo of 1.3 for UL of 2-sided 95%
CI, 6. uniform enrolment over 1.5 year with a maximum follow-up of 5 years (including the accrual period)
For 1o outcome, require: 8754 patients to observe at least 611 primary outcomes
Patients:
Screened N:
12076
Run-In N:
9618
– 2002 (Screening Failures)
– 456 (Withdrawals)
Randomized N:
9340
Completed N:
9042
– 106 (Run-In Failures)
– 172 (Withdrawals)
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Journal Club; Jun 23, 2016 – Shermaine Ngo
Data from patients who completed or discontinued the trial without having an outcome were censored from the day
of their last visit.
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Journal Club; Jun 23, 2016 – Shermaine Ngo
Eligibility
Inclusion Criteria:
-
-
T2DM
HbA1c > 7%
No previous drugs OR > 1 PO antihyperglycemic
agent OR insulin OR combo
> 50 yo with at least ONE CV condition or chronic
renal failure
o Prior MI
o Prior stroke or TIA
o Prior revascularization
o > 50% stenosis of coronary, carotid, or
lower extremity arteries
o Documented symptomatic CHD
o Documented asymptomatic cardiac
ischemia
o HF NYHA II-III
o Chronic kidney disease
> 60 yo with at least ONE CV RISK FACTOR
o Microalbuminuria or proteinuria
o Hypertension and left ventricular
hypertrophy
o Left ventricular systolic or diastolic
dysfunction
o Ankle-brachial index < 0.9
Exclusion Criteria:
-
-
-
-
Intervention
Outcomes
Type 1 diabetes
Calcitonin ≥50 ng/L
Use of a GLP-1 receptor agonist (exenatide, liraglutide
or other) or pramlintide or any DPP-4 inhibitor within
the 3 months prior to screening
Use of insulin other than human NPH insulin or longacting insulin analogue or premixed insulin within 3
months prior to screening. Short-term use of other
insulin during this period in connection with
intercurrent illness is allowed, at Investigator’s
discretion
Acute decompensation of glycemic control
Acute coronary or cerebrovascular event in the
previous 14 days
Currently planned coronary, carotid, or peripheral
artery revascularization
Chronic heart failure (NYHA class IV)
Current continuous renal replacement therapy
End-stage liver disease
History of solid organ transplant or awaiting solid
organ transplant
Malignant neoplasm
Family or personal history of multiple endocrine
neoplasia type 2 or familial medullary thyroid
carcinoma
Personal history of non-familial medullary thyroid
carcinoma
Products:
Liraglutide 6.0 mg/mL, 3 mL pen-injector for sc injection
Placebo, 3 mL pen-injector for sc injection
Store in refrigerator from +2 to +8oC
Median daily dose: 1.78mg liraglutide (IQR: 1.54-1.79)
Duration: 3.5 to 5 years of treatment
Mean of 3.5 years
Study visits: see 2. Flow Chart in Protocol
Primary composite endpoint:
Time from randomization to first occurrence of cardiovascular death, nonfatal MI or nonfatal stroke
Secondary endpoints:
First occurrence of an expanded composite outcome: CV death, nonfatal MI or nonfatal stroke,
revascularization, hospitalization for unstable angina, hospitalization for chronic heart failure
o CV mortality includes sudden cardiac death, death due to acute MI, death due to heart failure,
death due to stroke, death to other cardiovascular causes and deaths for which there was no clearly
documented non-vascular cause
Occurrence of non-cardiovascular or all-cause death
Each individual component of expanded composite CV outcome
Composite renal and retinal microvascular outcomes
o Nephropathy as: new onset of macroalbuminuria or a doubling of the serum creatinine level and an
eGFR of < 45 mL/min/1.73m2.
o Retinopathy: need for retinal photocoagulation or treatment with intravitreal agents, vitreous
hemorrhage or onset of diabetes-related blindness
Each individual component of composite microvascular outcomes
Neoplasms
Pancreatitis
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Journal Club; Jun 23, 2016 – Shermaine Ngo
Statistics
Required sample size: log-rank test – included full analysis set and an intention to treat principle
Non-inferiority margin: 1.3 for upper bound of 2 sided 95% CI
Analysis sets:
Full Analysis Set: includes all randomized subjects. Evaluated by principle of intention-to-treat
o Analysis of primary and secondary efficacy endpoint will be based on FAS
o Sensitivity analysis repeated "as treated" instead of "as randomised"
Per-Protocol Analysis Set: includes only data from trial periods of follow-up where subjects are exposed to
trial product. Includes additional 30 days after trial product discontinuation
Subgroup analyses: effect of sex, age (< 60 or > 60 yo) – not accurate since < 60 = CVD, BMI (< 30 or > 30),
HbA1c (< 8.3 or > 8.3), duration of diabetes (<11 or > 11 years), region (Europe, NA, Asia or other), race
(white, black, Asian or other), cardiovascular risk, CHF, severe chronic renal failure, severe to moderate
chronic renal failure and use of concomitant glucose medication and/or insulin on the primary composite
end point
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Journal Club; Jun 23, 2016 – Shermaine Ngo
Results –
Efficacy
Primary Endpoints:
*Composite outcome (time to first occurrence of cardiovascular death, non-fatal (including silent) myocardial
infarction, non-fatal stroke)
Liraglutide: 608/4668 patients (13%)
3.4 events/100 patient years
Placebo: 694/4672 patients (14.9%)
3.9 events/100 patient years
NNT: 66 /3 yrs
Hazard ratio: 0.87 (0.78 – 0.97)
P: 0.01
Individual outcomes: NSS
Except cardiovascular death
Fatal MI, Silent MI, Fatal Stroke: analysis not
pre-specified
* Secondary Endpoints:
Expanded Composite Outcome (cardiovascular death, non-fatal MI, non-fatal stroke, coronary revascularization or
hospitalization for unstable angina pectoris or hospitalization for heart failure)
Liraglutide: 948 (20.3%)
Placebo: 1062 (22.7%)
NNT: 42 /3.5 years
Hazard Ratio: 0.88 (0.81-0.96)
P: 0.005
Individual outcomes: NSS
Except CV death
*Microvascular events: Liraglutide: 355 (7.6%) vs. Placebo: 416 (8.9%) HR: 0.84 (0.73-0.97) P: 0.02
Retinopathy: Liraglutide: 106 (2.3%) vs. Placebo: 92 (2.0%)
HR: 1.15 (0.87-1.52) P: 0.33
Nephropathy: Liraglutide: 268 (5.7%) vs. Placebo: 337 (7.2%) HR: 0.78 (0.67-0.92) P: 0.003
o Defined as: new onset of macroalbuminuria or double of sCr level and an eGFR < 45
o NNT: 67 /3.5 years
Death from any cause: Liraglutide: 381 (8.2%) vs. Placebo: 447 (9.6%)
o NNT: 98/3 years
CV death:
Liraglutide: 219 (4.7%) vs. Placebo: 278 (6.0%)
Non-CV death: Liraglutide: 162 (3.5%) vs. Placebo: 169 (3.6%)
o NNT: 77 /3.5 years
HR: 0.85 (0.74-0.97) P: 0.02
HR: 0.78 (0.66-0.93) P: 0.007
HR: 0.95 (0.77-1.18) P: 0.66
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Journal Club; Jun 23, 2016 – Shermaine Ngo
Cardiovascular and Anti-diabetes medication at baseline and during trial:
Thiazides
Loop diuretics
Statins
Sulfonylureas
α-glucosidase
inhibitors
Thiazolidinediones
DPP-4 inhibitors
GLP-1RAs
SGLT-2 inhibitors
Insulin
Liraglutide
(N = 4668)
17.7%
17.6%
72.7%
50.6%
2.9%
Baseline
Placebo
(N = 4672)
16.8%
17.8%
71.4%
50.5%
2.6%
6.3%
<0.1%
0
43.6%
p-value
Introduced during trial
Placebo
p-value
(N = 4672)
5.1%
P < 0.001
8.2%
P < 0.01
9.6%
P = 0.010
10.8%
P < 0.001
3.1%
P < 0.001
0.28
0.80
0.87
0.92
0.34
Liraglutide
(N = 4668)
3.6%
6.5%
8.1%
7.6%
1.8%
6.0%
0.51
2.1%
3.4%
P < 0.001
<0.1%
<0.1%
45.5%
0.41
0.32
-
3.2%
1.9%
2.1%
28.6%
3.6%
3.0%
2.8%
43.2%
P = 0.24
P < 0.001
P = 0.046
SS
Sensitivity Analyses:
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Journal Club; Jun 23, 2016 – Shermaine Ngo
SS Sub-Group Analyses: Includes all randomized patients
Risk of CVD: p: 0.04
> 50 yo and established CVD (L: 536/3831 vs. P: 629/3767; HR: 0.83 (0.74-0.93))
> 60 yo and risk factors for CVD (L: 72/837 vs. P: 65/905 ; HR: 1.20 (0.86-1.67))
o Majority of patients fell into > 50 yo and established CVD
Severe or moderate renal disease: p: 0.01
< 60 ml/min/1.73 m2 (L: 172/1116 vs. P: 233/1042; HR: 0.69 (0.57-0.85))
> 60 ml/min/1.73 m2 (L: 436/3552 vs. P: 471/3630; HR: 0.94 (0.83-1.07))
o Sensitivity analysis of data for patients with eGFR < 60mL/min did not support a clinically
meaningful interaction
Results –
Safety
NNH:
- Any AEs: 67 /3.5 yrs (NSS)
- Serious AEs: 143 /3.5 yrs (NSS)
- Confirmed hypoglycemia:
53 /3.5 yrs (NSS)
- Severe hypoglycemia:
112 /3.5 yrs
- Acute gallstone dx:
84 /3.5 yrs
- Injection-site reactions:
250 /3.5 yrs
(Lexicomp: 3-14% - redness,
itching, rash)
-
Nausea: 84 /3.5 yrs
Vomiting: 167 /3.5 yrs
Diarrhea: 200 /3.5 yrs
Abdominal pain:
1000 /3.5 yrs
- Abdominal discomfort:
500 /3.5 yrs
- ↓ appetite:
1000 /3.5 yrs
- Pancreatic carcinoma:
500 /3.5 yrs (NSS)
Bottom Line
(Conclusion)
Author's Conclusion:
Among patients with type 2 diabetes who were at high risk for cardiovascular events while they were taking standard
therapy, those in the liraglutide group had lower rates of cardiovascular events and death from any cause than did
those in the placebo group.
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Journal Club; Jun 23, 2016 – Shermaine Ngo
Limitations
-
Application
to Clinical
Practice
Non-inferiority trial
Primary outcome: composite outcomes (individual outcomes are NSS)
~ 30% in North America (N: 2847)
o Subgroup analysis: HR: 1.01 (0.84 – 1.22)
Subgroup analysis mostly favouring liraglutide
Sponsored by Novo Nordisk (sponsor) was involved in all components of trial (e.g. design, analysis)
Add-on treatment excluded GLP-1 RA and DPP-4 inhibitors – but there were patients who were put on them
 may contribute to non-inferiority
Potential sources of un-blinding: weight loss, HbA1c reduction, SEs
o Supported by greater add-on diabetes therapy in placebo group
More patients on placebo had add-on diabetes treatment
Allowed duration of treatment ranged from 3.5 to 5 years
Data from patients who completed or discontinued the trial without having an outcome were censored from
the day of their last visit.
Strengths:
Fairly large study
Baseline characteristics were similar between groups
Attempt to standardize care over different sites
Low incidence of injection-site reactions
Treated by usual guidelines for patients with CVD (e.g. statins)
Reflective of efficacy of liraglutide in real practice
Sensitivity analyses – favoured liraglutide
Relatively low loss of patients (with minimal attrition bias)
For patients with type II diabetes with established cardiovascular disease and a HbA1c > 7%, liraglutide is non-inferior
to placebo in reducing composite cardiovascular outcomes including cardiovascular death, non-fatal MI and non-fatal
stroke.
The evidence in improving cardiovascular outcomes is not strong or large.
?Class effect
The magnitude of HbA1c reduction may not be sustained over time
Suggests benefits in nephropathy (mechanism unknown)
o Canadian labeling: current use is not recommended in moderate to severe renal impairment
o ?Safety in renal dysfunction (e.g. < 30 ml/min/1.73m2) and acute kidney injury
Supports evidence that it causes weight loss, low risk of hypoglycemia
Supports evidence of previous safety data and confirms long-term safety (minimum 3.5 years)
Supports its ability to reduce requirements for insulin
Supports long-term safety
Liraglutide: viable option for add-on diabetes therapy
2nd line to metformin
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