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).
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).
The submission nominated exenatide and sitagliptin as the
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
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|
|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
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.
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.