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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

- 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.

Rationale 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 Trial Design:- Multi-centred, international, randomised double-blind placebo-controlled trial - 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 controlo 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 codeso Interactive Voice/Web Response System

- Duration : 18 months of recruitment period followed by 42 months (3.5 years) from last subject randomizedo 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.

Objective "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

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Patient Population

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:

– 2002 (Screening Failures) – 106 (Run-In Failures) – 456 (Withdrawals) – 172 (Withdrawals)

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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Screened N: 12076

Run-In N: 9618

Randomized N: 9340

Completed N: 9042


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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 failureo Prior MIo Prior stroke or TIAo Prior revascularization o > 50% stenosis of coronary, carotid, or

lower extremity arterieso Documented symptomatic CHDo Documented asymptomatic cardiac

ischemiao HF NYHA II-IIIo Chronic kidney disease

- > 60 yo with at least ONE CV RISK FACTORo Microalbuminuria or proteinuriao Hypertension and left ventricular

hypertrophyo Left ventricular systolic or diastolic

dysfunctiono Ankle-brachial index < 0.9

Exclusion Criteria:- 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 long-acting 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

Intervention 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 Outcomes 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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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

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 yrsHazard 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 yearsHazard Ratio: 0.88 (0.81-0.96)

- P: 0.005

Individual outcomes: NSS - Except CV death

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*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 < 45o NNT: 67 /3.5 years

Death from any cause: Liraglutide: 381 (8.2%) vs. Placebo: 447 (9.6%) HR: 0.85 (0.74-0.97) P: 0.02o NNT: 98/3 years

- CV death: Liraglutide: 219 (4.7%) vs. Placebo: 278 (6.0%) HR: 0.78 (0.66-0.93) P: 0.007- Non-CV death: Liraglutide: 162 (3.5%) vs. Placebo: 169 (3.6%) HR: 0.95 (0.77-1.18) P: 0.66

o NNT: 77 /3.5 years

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Cardiovascular and Anti-diabetes medication at baseline and during trial:Baseline Introduced during trial

Liraglutide (N = 4668)

Placebo(N = 4672)

p-value Liraglutide (N = 4668)

Placebo(N = 4672)

p-value

Thiazides 17.7% 16.8% 0.28 3.6% 5.1% P < 0.001Loop diuretics 17.6% 17.8% 0.80 6.5% 8.2% P < 0.01Statins 72.7% 71.4% 0.87 8.1% 9.6% P = 0.010Sulfonylureas 50.6% 50.5% 0.92 7.6% 10.8% P < 0.001α-glucosidase inhibitors

2.9% 2.6% 0.34 1.8% 3.1% P < 0.001

Thiazolidine-diones

6.3% 6.0% 0.51 2.1% 3.4% P < 0.001

DPP-4 inhibitors <0.1% <0.1% 0.41 3.2% 3.6% P = 0.24GLP-1RAs 0 <0.1% 0.32 1.9% 3.0% P < 0.001SGLT-2 inhibitors - - - 2.1% 2.8% P = 0.046Insulin 43.6% 45.5% 28.6% 43.2% SS

Sensitivity Analyses:

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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

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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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)


Limitations - 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)

Application to Clinical Practice

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 impairmento ?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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affirm (atrial fibrillation follow-up investigation of ...€¦ · web viewliraglutide and...

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