Liraglutide (rys), solution for injection, 3 mL pre-filled injection pen, 6 mg per mL, Victoza®
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Product: Liraglutide (rys), solution for
injection, 3 mL pre-filled injection pen, 6 mg per mL,
Victoza®
Sponsor: Novo Nordisk Pharmaceuticals Pty
Ltd
Date of PBAC Consideration: November 2010
1. Purpose of Application
The submission sought an Authority Required (Streamlined) listing
for type 2 diabetes mellitus patients as:
1) Combination therapy with metformin and a sulfonylurea (triple
therapy)
2) Combination therapy with metformin or a sulfonylurea (dual
therapy).
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
On 26 August 2010, liraglutide was TGA registered as an adjunct to diet and exercise for treatment of adults with type 2 diabetes mellitus to achieve glycaemic control in:
- Dual combination therapy, added to metformin or a sulfonylurea, in patients with insufficient glycaemic control despite the use of maximally tolerated or clinically adequate doses of metformin or sulfonylurea monotherapy; and
- Triple combination therapy, added to metformin and a sulfonylurea in patients with insufficient glycaemic control despite dual therapy.
4. Listing Requested and PBAC’s View
Authority Required (Streamlined)
Combination therapy with metformin and a sulfonylurea.
Initiation of therapy, in combination with metformin and a
sulfonylurea, in type 2 diabetes mellitus patients who have an
HbA1c greater than 7% despite maximally tolerated doses of
metformin and a sulfonylurea.
The date of the HbA1c measurement, which must be no greater than 4
months old at the time of application, must be provided.
Continuation of therapy, in combination with metformin and a
sulfonylurea, in type 2 diabetes mellitus patients where the
patient has previously been issued with an authority prescription
for liraglutide or exenatide.
Authority Required (Streamlined)
Combination therapy with metformin or a sulfonylurea
Initiation of therapy, in combination with either metformin or a
sulfonylurea, in type 2 diabetes mellitus patients who have an
HbA1c greater than 7% and in whom a combination of metformin and a
sulfonylurea is contraindicated or not tolerated.
The date of the HbA1c measurement, which must be no greater than 4
months old at the time of application, must be provided.
Continuation of therapy, in combination with either metformin or a
sulfonylurea, in type 2 diabetes mellitus patients where the
patient has previously been issued with an authority prescription
for liraglutide, exenatide or a DPP-IV inhibitor.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Type 2 diabetes is a metabolic disorder characterised by
hyperglycaemia resulting from resistance to the action of insulin,
insufficient insulin secretion or both. Diet and lifestyle
modifications are the first steps in managing the disease, followed
by the addition of drug therapy with metformin. When diet,
lifestyle modifications and metformin monotherapy is inadequate in
controlling blood sugar levels, current treatment guidelines
recommend adding a sulfonylurea. If dual therapy with metformin and
a sulfonylurea is unsuccessful, insulin should preferably be added.
Instead of adding insulin, other options include the addition of a
thiazolidinedione (e.g. rosiglitazone, pioglitazone), acarbose, an
incretin (e.g. exenatide) or a glitinide (e.g. repaglinide).
The submission proposed that the place in therapy of liraglutide
would be as an alternative to the incretin class of therapies (i.e.
exenatide and gliptins).
6. Comparator
The submission nominated exenatide and sitagliptin as the
comparators.
The PBAC considered the main comparator to be exenatide from both a
clinical and economic perspective. See Recommendation and
Reasons.
7. Clinical Trials
The submission presented one randomised non-inferiority trial (also
powered to show superiority) (Study 1797 – LEAD 6) comparing
liraglutide 1.8 mcg given once daily plus an oral antidiabetic drug
(OAD) with exenatide 10 mcg given twice daily plus an OAD in
patients with type 2 diabetes mellitus (T2DM), and one randomised
trial (Study 1860) comparing liraglutide 1.2 mcg/day and 1.8
mcg/day with sitagliptin 100 mg/day combined with metformin in
patients with T2DM. The submission also presented the results of
six trials of various drug combinations in patients with T2DM as
supportive evidence.
Details of the published trials as presented in the submission are
as follows:
Published trials and associated reports presented in the
submission
| Trial ID/First author | Protocol title/Publication title | Publication citation |
| Direct randomised trials | ||
| Study 1797 (LEAD 6) Buse J, et al. | Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). | Lancet 2009; 374: 39–47 |
| Study 1860 Pratley RE, et al. | Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallel-group, open-label trial. | Lancet 2010; 375: 1447–56 |
| Supportive studies | ||
| Study 1573 (LEAD 3) Garber A, et al. | Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. | Lancet 2009; 373: 473-481 |
| Study 1436 (LEAD 1) Marre M, et al. | Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU). | Diabetic Medicine 2009; 26: 268-278. |
| Study 1572 (LEAD 2) Nauck M, et al. | Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. | Diabetes Care 2009; 32: 84-90. |
| Study 1574 (LEAD 4) Zinman B, et al. | Efficacy and safety of the human GLP-1 analog liraglutide in combination with metformin and TZD in patients with type 2 diabetes mellitus (LEAD-4 Met+TZD). | Diabetes Care 2009; 32: 1224-30 |
| Study 1697 (LEAD 5) Russell-Jones D, et al. | Liraglutide versus insulin glargine as add-on to metformin and a sulphonylurea in type 2 diabetes. A randomized controlled trial (LEAD-5: met+SU). | Diabetologia 2009; 52: 2046-2055. |
8. Results of Trials
Liraglutide or exenatide added to metformin and/or a sulfonylurea
(Study 1797: LEAD 6):
The primary outcome of Study 1797 was change from baseline in HbA1c
after 26 weeks of treatment.
The PBAC noted that Study 1797 demonstrated that liraglutide 1.8 mg
per day produced a statistically significant incremental benefit of
-0.33% (95% CI: -0.47, - 0.18) HbA1c over exenatide. Based on
pre-defined criteria, liraglutide 1.8 mg injected once daily was
found to be non-inferior and subsequently superior to exenatide 10
mcg injected twice daily with respect to change in HbA1c
from baseline (-1.2% (SD 0.88) vs -0.8% (SD 0.87)
respectively).
There were no clinical data comparing the efficacy of liraglutide
1.2 mg to exenatide 5 -10 mcg in Trial 1797. The clinical efficacy
of liraglutide 1.2 mg was estimated from a regression analysis. The
PBAC noted that only 9.7% of patients in this trial were taking
sulfonylureas as the OAD.
For the secondary outcome of proportion of patients reaching HbA1c
targets, a statistically significantly larger proportion of
liraglutide treated patients achieved the American Diabetes
Association (ADA) target (HbA1c less than 7%) and the American
Association of Clinical Endocrinologists (AACE) HbA1c target (HbA1c
less than or equal to 6.5%) than exenatide treated patients (odds
ratio (OR): 2.02 [95% CI 1.31, 3.11] and OR: 2.73 [95% CI 1.68,
4.43] respectively).
For the secondary outcome of hypoglycaemic episodes, there were no
patients in the liraglutide group and two patients (0.9%) in the
exenatide group experiencing a major hypoglycaemic event in the 26
week trial. There were significantly fewer minor hypoglycaemic
episodes with liraglutide treatment compared with exenatide
treatment (relative risk (RR): 0.55 [95% CI 0.34, 0.88]).
In addition, Study 1797 (LEAD-6) showed statistically significantly
larger reductions in fasting plasma glucose (FPG), triglyceride,
and free-fatty acid levels in liraglutide treated patients. There
were no statistically significant differences between liraglutide
and exenatide in fasting C-peptide, pro-insulin to insulin ratio,
total cholesterol, low-density lipoprotein, high-density
lipoprotein, the homeostasis model assessment (HOMA) Index of
insulin resistance, waist circumference, systolic and diastolic
blood pressure. The mean reduction in body weight from baseline to
end of treatment was similar in both the liraglutide and exenatide
groups (mean difference: -0.38 kg, 95% CI -0.99 kg to 0.23
kg).
Liraglutide or sitagliptin added to metformin (Study 1860):
The primary outcome of Study 1860 was change from baseline in HbA1c
after 26 weeks of treatment.
Liraglutide 1.8 mg/day and 1.2 mg/day in combination with metformin
produced statistically significantly larger reductions in HbA1c
than sitagliptin 100 mg/day combined with metformin (mean
difference -0.60 [95% CI -0.77, -0.43] and -0.34 [95% CI -0.51,
-0.16] respectively). The upper limit of the 95% CI for the mean
difference in HbA1c was less than the pre-defined non-inferiority
margin of 0.4%. Therefore, both liraglutide 1.8 mg/day and 1.2
mg/day were concluded to be both non-inferior to, and superior to
sitagliptin 100 mg/day. However, it was unclear whether the
incremental gain in reduction in HbA1c with liraglutide 1.2 mg was
clinically important. The data showed that liraglutide 1.8 mg/day
is more effective than liraglutide 1.2 mg/day in reducing
HbA1c.
For the secondary endpoint of hypoglycaemic episodes, there was
only one patient in the liraglutide 1.2 mg/day group and no
patients in the liraglutide 1.8 mg or sitagliptin groups
experiencing a major hypoglycaemic event in the 26 week trial.
There were no further major hypoglycaemic events reported in the
extension study.
There were more episodes of minor hypoglycaemic events in
liraglutide treated patients, however, the difference was only
statistically significant for the comparison of liraglutide 1.8
mg/day compared to sitagliptin 100 mg/day (p = 0.0206).
Both liraglutide 1.2 mg/day and 1.8 mg/day produced statistically
significantly greater reductions in fasting blood glucose (FPG)
levels from baseline to Week 26 compared to sitagliptin 100 mg/day.
Reductions in FPG levels from baseline were greatest for the
liraglutide 1.8 mg/day dose regimen.
Weight reduction in the liraglutide 1.2 mg/day and 1.8 mg/day
treatment groups was statistically significantly greater than with
sitagliptin 100 mg/day treatment, and was greater in the
liraglutide 1.8 mg/day treatment arm. The estimated mean reduction
in waist circumference from baseline to Week 26 was statistically
significantly greater in the two liraglutide treatment groups when
compared with sitagliptin.
There were no statistically significant differences between
liraglutide and sitaglitpin for reductions in systolic blood
pressure at Week 26. There was a statistically significantly
greater reduction in diastolic blood pressure in the sitagliptin
treatment group compared with the 1.8 mg/day liraglutide treatment
group.
There was no statistically significant difference in the effects of
liraglutide 1.2 mg/day and 1.8 mg/day compared with sitagliptin in
any of the fasting lipid parameters except for total cholesterol
(TC). There was no statistically significant difference between the
liraglutide and sitagliptin treatment groups with respect to
fasting insulin or the HOMA Index of insulin resistance from
baseline to the end of treatment. There was a statistically
significant difference between the liraglutide treatment groups
compared with the sitagliptin treatment group in fasting C-peptide,
pro-insulin to insulin ratio, and HOMA B%.
The results of the supportive studies generally affirmed the
comparable efficacy of liraglutide in reducing HbA1c when compared
directly with other antidiabetic agents in monotherapy, dual and
triple therapy. However, there was no difference in mean change in
HbA1c for liraglutide 1.2 mg and 1.8 mg in combination with
metformin versus glimepiride in combination with metformin (Trials
1572 [LEAD 2] and 1796).
Quality of life (Patient reported outcomes assessed by Diabetes
Treatment Satisfaction Questionnaire (DTSQ)):
In Study 1797 (LEAD-6), the overall treatment satisfaction
increased in both liraglutide and exenatide treatment groups from
baseline to end of treatment at Week 26, but the increase was
statistically significantly greater in the liraglutide group
compared to the exenatide group (p < 0.0001). Decreases in
perceived frequency of hyperglycaemia and hypoglycaemia were
observed in both treatment groups, but the decreases were
statistically significantly greater in the liraglutide group
compared to the exenatide group (p = 0.0021 and p = 0.0401,
respectively).
In Study 1860, overall treatment satisfaction increased in all
treatment groups from baseline but the increase was statistically
significantly greater in the liraglutide 1.8 mg/day treatment arm
compared to the sitagliptin 100 mg/day treatment arm (p = 0.03).
There was no statistically significant difference between the
liraglutide 1.2 mg/day treatment arm and the sitaglitpin 100 mg/day
treatment arm (p = 0.3962) for overall treatment
satisfaction.
In Study 1797 there were similar numbers of patients reporting
adverse events in the liraglutide treatment group (74.9%) and the
exenatide treatment group (78.9%). Reports of serious adverse
events were 5.1% in the liraglutide treatment group and 2.6% in the
exenatide treatment group. Withdrawal from the trial because of
adverse events was slightly lower in the liraglutide treatment
group (9.8%) compared with the exenatide group (13.4%). No deaths
were reported in Study 1797. Similar total numbers of patients
reported gastrointestinal side effects (45.5% liraglutide and 42.7%
exenatide) and specifically nausea (25.5% liraglutide and 28.0%
exenatide). The duration of nausea was longer in the exenatide
treatment group (median duration 57 days) compared with the
liraglutide treatment group (median duration 14 days).
In Study 1860, the overall proportion of subjects reporting adverse
events was slightly higher in the liraglutide 1.2 mg (66.1%) and
liraglutide 1.8 mg (72.9%) treatment groups than the sitagliptin
treatment group (58%). This difference was mainly attributable to
the higher number of gastrointestinal adverse events associated
with liraglutide treatment (33.0% in liraglutide 1.2 mg; 40.4% in
liraglutide 1.8 mg) compared with sitagliptin treatment (21.0%).
Reports of serious adverse events were comparable across all
treatment groups (2.7% in liraglutide 1.2 mg; 2.8% in liraglutide
1.8 mg and 1.8% in sitagliptin). Withdrawal from the trial because
of adverse events was lower in the sitagliptin treatment group
(1.8%) compared with the two liraglutide treatment groups (6.2%
liraglutide 1.2 mg; 6.8% liraglutide 1.8 mg). There were two deaths
reported in Study 1860, one in the liraglutide 1.8 mg treatment
group and one in the sitagliptin treatment group.
9. Clinical Claim
The submission claimed liraglutide to be superior in terms of
comparative effectiveness and equivalent in terms of comparative
safety over exenatide and sitagliptin.
For PBAC’s view, see Recommendations and
Reasons.
10. Economic Analysis
The submission presented a modelled economic evaluation, based on
the direct randomised trials and using the CORE Diabetes Model to
project the long-term outcomes of treatment. The type of economic
evaluation presented was a cost-utility analysis.
The time horizon in the modelled economic evaluation was 35 years.
The model assumed that treatment with liraglutide and exenatide (or
sitagliptin) continues for five years, after which patients are
switched to basal insulin. After switching to insulin, all patients
have the same HbA1c (7%); and HbA1c progresses equally for the
treatment groups, according to the United Kingdom Prospective
Diabetes Study (UKPDS) regression equation (Clarke, 2004).
Based on the results of Study 1797, the results of the economic
evaluation comparing liraglutide 1.8 mg once daily with exenatide
10 mcg twice daily, calculated the incremental cost per quality
adjusted life year (QALY) gained to be in the range of $45,000 -
$75,000.
Based on the results of Study 1860, the results of the economic
evaluation comparing liraglutide 1.2 mg once daily with sitagliptin
100 mg/day calculated the incremental cost per QALY gained to be in
the range of $15,000 - $45,000. The economic evaluation comparing
liraglutide 1.8 mg/day with sitagliptin 100 mg/day also calculated
the incremental cost per QALY gained to be in the same range.
The submission presented a weighted cost effectiveness analysis,
based on the assumption that liraglutide substitution will be 50%
from exenatide and 50% from sitagliptin (assuming 25% compared with
liraglutide 1.2 mg and 25% compared with liraglutide 1.8 mg). The
weighted incremental cost per QALY gained was in the range of
$45,000 - $75,000. No justification was provided for this
weighting.
The results of sensitivity analyses indicated that the key drivers
of the model were the cost of treatment, HbA1c effect, discount
rate and time horizon. The results of the sensitivity analyses
indicated that the model was most sensitive to changes in HbA1c
effect. A sensitivity analysis conducted during the evaluation
showed that when non-statistically significant differences were
excluded, the ICER for the comparison with exenatide increased to
between $75,000 - $105,000.
For PBAC’s view on the economic modelling, see
Recommendation and Reasons.
11. Estimated PBS Usage and Financial Implications
The financial cost per year to the PBS was estimated in the
submission to be in the range of $30 - $60 million per year in Year
5. This was a likely underestimate. The submission’s
estimates were sensitive to increases in market share (uptake rate)
and rates of compliance. When the uptake rate of liraglutide in the
DPP4 and exenatide pool was increased by 10% the overall cost to
the PBS/RPBS increased by approximately $10 million in Year 5 of
listing. When the rate of compliance was increased by 10% the
overall cost to the PBS/RPBS increased by approximately $6 million
in Year 5 of listing.
12. Recommendation and Reasons
The PBAC considered the requested restriction to be appropriate,
although a streamlined Authority listing was not considered
appropriate for a member of this new class of drugs (GLP1
analogues).
The submission’s nominated comparator of a 50:50 split
between exenatide and sitagliptin was not accepted. The PBAC noted
that exenatide, the appropriate comparator, is a pharmacological
analogue of liraglutide and the proposed 50:50 split assumes that,
effectively, 75% of the therapy to be substituted by liraglutide
would be oral, given that exenatide was recommended on an almost
50:50 split between insulin glargine and a glitazone. Such a 75:25
split was not considered reasonable. The PBAC thus considered the
main comparator to be exenatide from both a clinical and economic
perspective.
The PBAC noted that Study 1797 demonstrated that liraglutide 1.8 mg
per day produced a statistically significant incremental benefit of
-0.33% HbA1c over exenatide. The PBAC considered the question of
whether this difference was clinically relevant. The Pre-PBAC
Response to this issue claimed that international regulatory
guidance documents and expert clinical advice indicated that it was
both clinically important and clinically meaningful. The PBAC noted
that a 0.3% difference in HbA1c in the regulatory guidance
documents refers to both the non-inferiority margin and a
clinically meaningful reduction in HbA1c.
Further, the Pre-PBAC Response claimed that there is a linear
relationship between lowering HbA1c and the reduction in the risk
of diabetes-related complications and that analysis of the UKPDS
demonstrates that there is no threshold effect on lowering HbA1C.
However, the PBAC was not convinced that a purely linear
relationship existed across all levels of HbA1c and therefore
considered that uncertainty remained over the extent of clinical
benefit associated with this 0.33% difference. Given the clinical
findings above and the uncertainty of the incremental benefits of
liraglutide over exenatide on clinical endpoints, overall, there
was doubt about the submission's claims of superiority over
exenatide.
The PBAC also noted that there were no clinical data comparing the
efficacy of liraglutide 1.2 mg to exenatide 5-10 mcg in Trial 1797.
The clinical efficacy of liraglutide 1.2 mg was estimated from a
regression analysis and applied in the economic model as a
sensitivity analysis. In addition, only 9.7% of patients in this
trial were taking sulfonylureas as the OAD. Therefore there are
limited data on which to assess treatment with the combination of
liraglutide and a sulfonylurea compared to exenatide plus a
sulfonylurea.
The PBAC noted that there were similar numbers of adverse events
between liraglutide and exenatide.
The PBAC noted that there may be a benefit of once daily injections
for liraglutide compared with twice daily injections for exenatide,
although the submission had not examined this factor.
The PBAC noted a number of uncertainties in the economic model. In
particular, the model inappropriately included non-statistically
significant differences in trial results, such as systolic and
diastolic blood pressure and lipid profiles. The PBAC noted the
sensitivity analysis excluding non-statistically significant
differences increased the ICER for the comparison with exenatide
from a base case in the range of $45,000 - $75,000 to a range of
$75,000 - $105,000.
Further, the lack of transparency of the CORE model (although
inputs in the model can be altered, it was not possible to
determine how the inputs were transformed into the model outputs)
meant that, without the possibility of appropriately independent
verification, there was overall uncertainty in the modelled
prediction of the treatment benefit of liraglutide. The PBAC agreed
that the model’s extrapolated benefits in overall survival
and quality adjusted survival were uncertain in the context of the
small advantage of 0.33% in HbA1c.
Given the clinical and economic uncertainties, the PBAC considered
that, at best, the ICER would be in excess of $70,000 per QALY. The
PBAC therefore rejected the submission because of an unacceptably
high and uncertain cost effectiveness ratio.
Recommendation
Reject
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
Novo Nordisk is disappointed with the decision of the PBAC not to
recommend listing of liraglutide based on the first submission.
Novo Nordisk maintains that exenatide and sitagliptin should both
be appropriate comparators as they are both members of the incretin
class of pharmacotherapies. Novo Nordisk does not agree that it was
inappropriate to include all treatment effects (including
non-significant outcomes) in the model as it is important to
include all predictors of long term outcomes within a model to
ensure the most accurate projections of long-term clinical benefit.
Novo Nordisk will however continue to work closely with the DoHA to
address the outstanding issues in order to secure a listing of
liraglutide on the PBS in as timely a manner as possible.
