Linagliptin, tablet, 5 mg, Trajenta®
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Public Summary Document
Product: Linagliptin, tablet, 5 mg,
Trajenta®
Sponsor: Boehringer Ingelheim Pty Ltd
Date of PBAC Consideration: July 2011
1. Purpose of Application
The submission sought an Authority required (STREAMLINED) listing
for treatment of patients with type 2 diabetes in combination with
metformin or a sulfonylurea.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Linagliptin was TGA registered on 1 November 2011 and is indicated
for treatment of adult patients with type 2 diabetes mellitus to
improve glycaemic control in conjunction with diet and exercise, as
add on to metformin, sulphonylureas or metformin plus
sulphonylureas.
4. Listing Requested and PBAC’s View
Authority Required (STREAMLINED)
Dual oral combination therapy with metformin or a sulfonylurea.
Type 2 diabetes, in combination with either metformin or a sulfonylurea, in a patient whose HbA1c is greater than 7% prior to initiation of a dipeptidyl peptidase 4 inhibitor (gliptin), a thiazolidinedione (glitazone) or a glucagon-like peptide-1 despite treatment with either metformin or a sulfonylurea and where a combination of metformin and a sulfonylurea is contraindicated or not tolerated.
The date and level of the qualifying HbA1c must be documented in the patient's medical records at the time treatment with a gliptin, a glitazone or a glucagon-like peptide-1 is initiated. The HbA1c must be no more than 4 months old at the time treatment with a gliptin, a glitazone or a glucagon-like peptide-1 is initiated.
Blood glucose monitoring may be used as an alternative assessment to HbA1c levels in the following circumstances: (a) clinical conditions with reduced red blood cell survival, including haemolytic anaemias and haemoglobinopathies; and/or (b) red cell transfusion within the previous 3 months.
A patient in these circumstances will be eligible for treatment
where blood glucose monitoring over a 2 week period shows blood
glucose levels greater than 10 mmol per L in more than 20% of
tests. The results of this blood glucose monitoring, which must be
no more than 4 months old at the time of initiation of treatment
with a gliptin, a glitazone or a glucagon-like peptide-1, must be
documented in the patient's medical records.
The PBAC noted the requested restriction was consistent with those
for other medicines currently listed on the PBS for this
condition.
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 exercise are the
first steps in managing the disease, followed by the addition of
drug therapy with metformin. When diet and exercise modifications
and metformin monotherapy is inadequate in controlling blood
glucose, current treatment guidelines recommend adding a
sulfonylurea. If dual therapy with metformin and a sulfonylurea is
unsuccessful, insulin can be added. Other options include glucagon
like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase-4
(DPP-4) inhibitors, thiazolidinediones, alpha-glucosidase
inhibitors, or meglitinides.
The submission proposed that the place in therapy of linagliptin is
an alternative therapy to sitagliptin or vildagliptin in the
current clinical treatment algorithm for Type 2 diabetes, after
diet and exercise, metformin and then a sulfonylurea have
failed.
6. Comparator
The submission nominated sitagliptin as the main comparator. The
PBAC agreed that this is appropriate.
7. Clinical Trials
Linagliptin plus metformin
The submission presented a meta-analysis of two randomised trials (1218.6 and 1218.17)
comparing linagliptin plus metformin with placebo plus metformin. This meta-analysis
was compared to three meta-analyses using four randomised trials comparing sitagliptin
plus metformin with placebo plus metformin (Charbonnel 2006, Goldstein 2007; Raz 2008
and Scott 2008).
A supplementary analysis of linagliptin plus metformin compared to sitagliptin plus
metformin was also included in the submission. This indirect comparison has a different
comparator arm and for that reason was not included in the primary analysis. This
indirect comparison used meta-analysed Trials 1218.20 and 1218.6 and compared it to
Nauck 2007.
Linagliptin plus a sulfonylurea
The submission compared one randomised trial (1218.35) comparing linagliptin plus
a sulfonylurea and placebo plus a sulfonylurea to one randomised trial (Hermansen
2007) with sitagliptin plus a sulfonylurea and placebo plus a sulfonylurea.
Details of the trials and associated reports published at the time of the submission
are shown in the table below.
| Trial ID / First author | Protocol title / Publication title | Publication citation |
|---|---|---|
| Placebo controlled sitagliptin trials with metformin | ||
| Placebo controlled sitagliptin trials with a sulfonylurea | ||
| Charbonnel 2006 | Randomised, double blind, parallel group study evaluating the efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. | Diabetes care 29, 2638-2643. |
| Goldstein 2007 Goldstein, B. J. et al Williams-Herman, D. et al. Williams-Herman, D. et al |
Randomised, double blind, parallel group study evaluating the effect of initial combination
therapy with sitagliptin, and metformin on glycemic control in patients with type
2 diabetes. A 24 Week Study. Randomised, double blind, parallel group study evaluating the efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes: A 54-week study. Randomised, double blind, parallel group study evaluating the efficacy and safety of sitagliptin and metformin as initial combination therapy and as monotherapy over 2 years in patients with type 2 diabetes. |
Diabetes care 30, 1979-1987. Current Medical Research and Opinion 25(3), 569-583. Diabetes, Obesity and Metabolism 12(5), 442-451. |
| Raz 2008 | Randomised, double blind, parallel group study evaluating the efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. A 30 Week study. | Current Medical Research and Opinion 24, 537-550 |
| Scott 2008 | Randomised, double blind, parallel group study evaluating the efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes. | Diabetes, Obesity and Metabolism 10(10), 959-969. |
| Hermansen 2007 | Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. | Diabetes, obesity & metabolism 9, 733-745. |
| Nauck 2007 Seck 2010 |
Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared
with a sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled
on metformin alone: A randomised, double-blind, non-inferiority trial. Safety and efficacy of treatment with sitagliptin or glipizide in patients with type 2 diabetes inadequately controlled on metformin: A 2-year study. |
Diabetes, Obesity and Metabolism 9(2), 194-205. International Journal of Clinical Practice 64(5), 562-576. |
8. Results of Trials
Linagliptin in combination with metformin
The submission undertook a full analysis set comparison as well as a per protocol
comparison. Both comparisons of linagliptin plus metformin resulted in significant
reductions in HbA1c compared to placebo. Similarly, the trials comparing sitagliptin
plus metformin and placebo plus metformin (Charbonnel 2006, Scott 2008) demonstrated
significant reductions for HbA1c for the sitagliptin arm. The indirect comparison
resulted in a reduction in HbA1c, below the 0.4% minimum clinically important difference
(MCID).
The submission suggested that the proportion of patients that reported an adverse
event was similar in the linagliptin plus metformin arms compared to the placebo plus
metformin arms. The submission undertook relative risk and risk difference analyses
for all adverse events, serious adverse events or adverse events leading to discontinuation
and suggested that there is no significant difference between the linagliptin plus
metformin arm or the placebo plus metformin arm. In addition, indirect comparisons
were undertaken comparing the proportion of subjects reporting any adverse event,
serious adverse event, cardiovascular adverse events and serum lipids, between linagliptin
and sitagliptin. These indirect analyses showed that there were no significant differences
between linagliptin and sitagliptin.
Linagliptin in combination with a sulfonylurea
The submission undertook a full analysis set comparison as well as a per protocol
comparison. The comparison of linagliptin plus sulfonylurea resulted in a significant
reduction in HbA1c compared to placebo. Similarly the comparison of sitagliptin plus
a sulfonylurea and placebo plus a sulfonylurea demonstrated significant reductions
in HbA1c for the sitagliptin arm. The indirect comparison resulted in a weighted mean
difference just exceeding the 0.4% MCID.
The submission suggested that the proportion of patients that reported an adverse
event was similar in the linagliptin plus a sulfonylurea arm compared to the placebo
plus a sulfonylurea arm. The submission undertook relative risk and risk difference
analyses for all adverse events, serious adverse events or adverse events leading
to discontinuation and claimed that there is no significant difference between the
linagliptin plus a sulfonylurea arm or the placebo plus a sulfonylurea arm. Indirect
comparisons were undertaken comparing the proportion of subjects with adverse events
and serious adverse events between linagliptin and sitagliptin. These analyses showed
that there was no significant difference between linagliptin and sitagliptin.
The submission provided data from four trials in the extended assessment of safety
of linagliptin. A 54-week interim report of trial 1218.20, a final report of 1218.23
and an interim report at 42-54 weeks of a 78 week study (trial 1218.40). Trial 1218.PI
was a pre-specified meta-analysis of cardiovascular safety. It combined data from
eight linagliptin trials. The submission also provided a summary of clinical safety
presented to the TGA which included over 30 studies representing over 6,000 subjects.
These studies indicated that there were comparable rates of adverse events in linagliptin
treated participants compared to placebo treated participants. These do not appear
to identify any additional adverse events not reported in the pivotal studies.
For PBAC’s comments on these results, see Recommendation and Reasons.
9. Clinical Claim
The submission claimed linagliptin plus metformin is non-inferior in terms of efficacy
and safety to sitagliptin plus metformin.
The submission claimed linagliptin plus a sulfonylurea is non-inferior in terms of
efficacy compared to sitagliptin plus sulfonylurea. The submission claimed that linagliptin
plus a sulfonylurea is non-inferior in terms of safety compared to sitagliptin plus
sulfonylurea.
For PBAC’s view, see Recommendation and Reasons.
10. Economic Analysis
The submission presented a cost minimisation analysis. The equi-effective doses were estimated as linagliptin 5mg daily and sitagliptin 100mg daily. This was accepted by the PBAC on the basis of the clinical data.
11. Estimated PBS Usage and Financial Implications
The likely number of prescriptions per year was estimated in the submission as between
100,000 and 200,000 in Year 5 of listing at a net cost per year to the PBS of less
than $10 million in Year 5.
The submission estimated small additional costs to the PBS on the basis that linagliptin
is presented in a 30-day pack compared with sitagliptin in a 28-day pack resulting
in a requirement to fill 12.2 prescriptions of linagliptin per year instead of 13.0
prescriptions per year with sitagliptin, and therefore on average one less co-payment
each year.
12. Recommendation and Reasons
The PBAC was of a mind to recommend listing of linagliptin on a cost minimisation
basis compared with sitagliptin. However, in the absence of a decision by the TGA
Delegate on the registration of linagliptin, the PBAC deferred a final recommendation.
The PBAC agreed to finalise its decision on the listing of linagliptin following the
receipt of a positive TGA Delegate’s Summary.
On the basis of the clinical data, the equi-effective doses are estimated as linagliptin
5mg daily and sitagliptin 100mg daily.
For the comparison with sitagliptin when both are used in comparison with metformin,
the submission presented one meta-analysis of two randomised trials (1218.6, 1218.17)
comparing linagliptin plus metformin with placebo plus metformin. This meta-analysis
is compared to three meta-analyses using four randomised trials comparing sitagliptin
plus metformin with placebo plus metformin (Charbonnel 2006, Goldstein 2007; Raz 2008
and Scott 2008). The PBAC noted that the pooled indirect comparison of effect based
on the primary outcome of change in HbA1c was within the pre-specified non-inferiority
margin for MCID in HbA1c of 0.4% and that it also fell within a MCID of 0.3%. This
indirect analysis therefore demonstrates that linagliptin is non-inferior to sitagliptin
with respect to diabetes control when both are used in combination with metformin.
For the comparison with sitagliptin when both are used in combination with a sulfonylurea,
the submission presented one randomised trial (1218.35) comparing linagliptin plus
a sulfonylurea and placebo plus a sulfonylurea to one randomised trial (Hermansen
2007) with sitagliptin plus a sulfonylurea and placebo plus a sulfonylurea. The confidence
interval of the indirect analysis for HbA1c was outside the MCID and thus non-inferiority
was not demonstrated. The submission suggested that the reason for not being able
to demonstrate non-inferiority of linagliptin with a sulfonylurea is that there was
only one trial, per arm, available to analyse and that there was a difference in the
drugs and dose of the sulfonylurea. Whilst non-inferiority is neither demonstrated
nor excluded by this comparison the PBAC accepted that linagliptin is likely to be
non inferior to sitagliptin when both are use in combination with a sulfonylurea.
The PBAC agreed that the safety results for linagliptin and sitagliptin suggested
non inferiority in this regard but noted there is uncertainty as long term data are
lacking.
The submission estimated small additional costs to the PBS on the basis that it is
presented in a 30 day pack compared with sitagliptin in a 28-day pack.
The PBAC also recommended that linagliptin be included in the PBS medicines for prescribing
by nurse practitioners.
Recommendation:
Defer
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
The sponsor does not wish to provide any comments
