Download Commissioning Support DPP-4 inhibitors (`Gliptins`)

Commissioning Support
DPP-4 inhibitors (‘Gliptins’):
Sitagliptin (Januvia®), Vildagliptin (Galvus®), Saxagliptin
(Onglyza®), Linagliptin (Trajenta®▼), Alogliptin
(Vipidia®▼)
For the treatment of type 2 diabetes
Commissioning guidance points for consideration:
 The management of patients with type 2 diabetes involves an individualised, multifactorial approach that
addresses blood pressure, blood lipids and lifestyle issues, as well as blood glucose. Controlling blood glucose
requires a careful balance taking into account clinical, physical, psychological and social needs, and the
individual’s own preferences for care.
 If a gliptin is to be used, it is advised that the gliptin is selected based on the appropriate licensed indications,
with the lowest acquisition cost
 No significant differences were reported between the gliptins with respect to blood glucose-lowering efficacy
against other oral diabetic treatments in systematic review evidence, or in one RCT head-to-head comparison of
sitagliptin and saxagliptin.
 NICE guidance (CG87) states that treatment with DPP-4 inhibitor therapy (sitagliptin and vildagliptin were
available for review at the time of publication) should only be continued if the patient has had a beneficial
metabolic response (a reduction of at least 0.5% [5 mmol/mol] in HbA1c [glycosylated haemoglobin]) in 6 months.
An update to this guidance is expected in August 2015.
 Commissioners should ensure that adequate review/audit arrangements are in place to monitor metabolic
response in patients treated with DPP-4 inhibitors or other oral antidiabetic drugs covered by NICE guidance
(target reduction of 5 mmol/mol or 0.5% HbA1c [pioglitazone, dapagliflozin], target reduction of 11 mol/mol or 1%
HbA1c [exenatide, liraglutide]). Weight-loss targets of ≥ 3% of initial body weight after 6 months are additionally
specified when exenatide and liraglutide are used as part of a triple therapy regimen.
The National Diabetes Audit 2011/12 recommended that all CCGs review their overall management of patients with
type 2 diabetes, including results for the proportions of patients achieving all three NICE recommended targets for
glucose control, blood pressure and serum cholesterol levels (all QOF incentivised):
 Blood glucose control is a complex balancing act. The MeReC bulletin on diabetes suggests that reducing
HbA1c to about 59 mmol/mol (7.5%) seems optimal.
 Blood pressure: <140/80 in all; <130/80 if complications
 Cholesterol: <4mmol/ or <5mmol/l
MTRAC considered the gliptins as a class to place them in context in the treatment of type 2 diabetes
Description of the technology
The dipeptidyl peptidase 4 (DPP-4) inhibitors act on
DPP-4, an enzyme responsible for the inactivation of
the incretin hormones including glucagon-like peptide 1
and glucose-dependent insulinotropic peptide, which
are released from gut cells in response to a meal.
These hormones stimulate insulin release and reduce
glucagon secretions thereby reducing blood glucose
levels.
Five DPP-4 inhibitors are licensed for use for the
treatment of type 2 diabetes in the UK; their licensed
indications are summarised in Table 1 below.
Clinical evidence for efficacy and safety
1
A recent systematic review of the efficacy of all five
DPP-4 inhibitors compared with placebo or standard
treatment for type 2 diabetes found that, as
monotherapy compared with placebo, weighted mean
changes in HbA1c ranged from -0.59% to -0.8% (6 to 8
mmol/mol) across the DPP-4 inhibitors. As dual
therapy with metformin or a sulfonylurea vs. metformin
or a sulfonylurea alone, mean HbA1c changes were
1
-0.47 to -0.84% (5 to 9 mmol/mol).
There is little comparative evidence for efficacy
between gliptins. One double-blind phase 3 RCT (n =
801) showed that, as add-on treatment to metformin,
saxagliptin was non-inferior to sitagliptin, with weighted
mean changes in HbA1c of 5 to 6 mmol/mol (-0.42% and
2
-0.59% respectively) after 18 week’s treatment.
Hypoglycaemia occurred in about 3% of all patients and
body weight decreased from baseline values by a mean
of 0.4 kg in all patients.
Evidence that DPP-4 inhibitors improve macrovascular
or microvascular outcomes is lacking. Two recently
published, manufacturer-sponsored, large phase IV
3
4
RCTs (SAVOR TIMI-53; EXAMINE ), involving
saxagliptin or alogliptin, found that neither increases nor
reduces the risk of cardiovascular events in the short
3,4
Event rates
term (median 1.5 to 2 years’ follow up).
(composite of CV death, non-fatal MI, or non-fatal
ischaemic stroke) were about 7% over two years in
patients (with established CV disease or multiple CV
3
risk factors) in the SAVOR-TIMI trial , and 11-12% of
patients with diabetes and recent acute coronary
4
syndrome in the EXAMINE trial.
WARNING: This sheet should be read in conjunction with the Summaries of Product Characteristics. This guidance is based upon the published
information available in English at the time the drugs were considered. It remains open to review in the event of significant new evidence emerging.
School of Pharmacy, Keele University, Keele, Staffordshire ST5 5BG
©Midlands Therapeutics Review & Advisory Committee
Tel: 01782 734131 Email: [email protected] Web: www.mtrac.co.uk
Date: May 2014
Triple oral therapy:
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Add-on to insulin
(with or without metformin) when diet
and exercise plus a stable dose of
insulin do not provide adequate
glycaemic control

thiazolidinedione and
metformin when use of a
thiazolidinedione is appropriate
and when diet and exercise plus
dual therapy with these medicinal
products do not provide adequate
glycaemic control

sulfonylurea and metformin
when diet and exercise plus dual
therapy with these medicinal
products do not provide adequate
glycaemic control

thiazolidinedione, in patients with
insufficient glycaemic control and
for whom the use of a
thiazolidinedione is appropriate
sulfonylurea, in patients with
insufficient glycaemic control
despite maximal tolerated dose of
a sulfonylurea and for whom
metformin is inappropriate due to
contraindications or intolerance
Sitagliptin
100 mg
(Januvia)
Vildagliptin
100 mg
(Galvus)
Saxagliptin
5 mg
(Onglyza)
Linagliptin 5mg
▼
(Trajenta )
Alogliptin
25 mg
▼
(Vipidia )
Dual oral therapy:
metformin, in patients with
insufficient glycaemic control despite
maximal tolerated dose of
monotherapy with metformin
Usual daily
doses quoteda
Lower doses
may be
considered in
combination with
a sulfonylurea or
insulin, or in
moderate renal
impairment*
Hyperlinks to
Summaries of
Product
Characteristics
(SPC)
Monotherapy
in patients inadequately controlled by
diet and exercise alone and for whom
metformin is inappropriate due to
contraindications or intolerance
Table 1: Licensed indications of DPP-4 inhibitors available in the UK
*All gliptins require dose adjustment for moderate and severe renal impairment with exception of linagliptin. No dose adjustments required for
mild and moderate hepatic impairment with exception of vildagliptin, which should not be used in patients with hepatic impairment.
Adverse events
A systematic review of longer-term safety of DPP-4
inhibitors (up to 104 weeks) reported no significant
difference in adverse event rates or discontinuation
from treatment due to an adverse event between DPP5
4 inhibitors and comparators. The review also found
no significant difference in rates of hypoglycaemia
between DPP-4 inhibitors and comparators unless coadministered with a sulfonylurea or insulin, where the
rate was higher. This is a known risk and is reflected
in the dosing guidance in the SPCs (links in Table 1).
In September 2012, the MHRA described an increased
risk of acute pancreatitis for all approved DPP-4
inhibitors in post-marketing reports and clinical data.
Reporting rates for pancreatitis with DPP-4 inhibitors
ranged from 1/1000 to 1/100 patients receiving the
drug. A 2013 EMA review of findings concerning
pancreatitis and precancerous, pancreatic duct
metaplasia in patients with type 2 diabetes treated with
DPP-4 inhibitors concluded that “presently available
data do not confirm recent concerns over an increased
risk of pancreatic adverse events with these
medicines.” Regarding pancreatic cancer, they stated
that “data from clinical trials do not indicate an
increased risk with these medicines. However, the
number of events is too small to draw final
conclusions”. The European Commission has funded
two large ongoing studies evaluating the risk profile of
diabetes treatments in general, and specifically their
risk profile in relation to the pancreas (results expected
3
4
in 2014). In the SAVOR TIMI-53 and EXAMINE trials,
rates of acute pancreatitis were low, with similar rates
of events in the drug and placebo groups. The
incidence of pancreatic cancer was 5 and 12 cases,
a
respectively, in the drug and placebo groups in the
SAVOR TIMI-53 trial, with no reports in either group in
3,4
the EXAMINE trial.
Considerations for the NHS
Table 2: Cost information
Cost per
patient
per year
Patent
b
expiry year
Januvia
£434
2022*
Vildagliptin 100 mg
Galvus
£414
2019*
Saxagliptin 5 mg
Onglyza
£412
2021†
Linagliptin 5 mg
Trajenta
£434
2021†
£347
2023†
Generic name
a
(daily dose )
Brand
name
Sitagliptin 100 mg
Alogliptin 25 mg
Vipidia
▼
▼
[Prices from MIMS, November 2014]
References
1. Craddy P et al. Comparative Effectiveness of
Dipeptidylpeptidase-4 Inhibitors in Type 2 Diabetes: A
Systematic Review and Mixed Treatment Comparison.
Diabetes Ther 2014.
2. Scheen AJ et al. Efficacy and safety of saxagliptin in
combination with metformin compared with sitagliptin in
combination with metformin in adult patients with type 2
diabetes mellitus. Diabetes Metab Res Rev 2010;
26(7):540-549.
3. Scirica BM et al. Saxagliptin and cardiovascular
outcomes in patients with type 2 diabetes mellitus. N Engl
J Med 2013; 369(14):1317-1326.
4. White WB et al. Alogliptin after acute coronary syndrome
in patients with type 2 diabetes. N Engl J Med 2013;
369(14):1327-1335.
5. Goossen K et al. Longer term safety of dipeptidyl
peptidase-4 inhibitors in patients with type 2 diabetes
mellitus: Systematic review and meta-analysis. Diabetes,
Obesity and Metabolism 2012; 14(12):1061-1072.
The doses shown do not represent the full range that can be used, and they do not imply therapeutic equivalence.
Patent expiry dates are estimates and are subject to change e.g. extension due to renewal of marketing authorisation; *Patent expiry dates
reported in UKMi Patents expiry database; † Patent expiry dates estimated from SPC dates.
b