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Rejected
ATC codes:
A10AE04
Indication
Type 1 diabetes mellitus
ICD11 code:
5A10
INN
Insulin glargine
Medicine type
Biological agent
List type
Core
Formulations
Parenteral > General injections > SC:
100 units per mL
Sex
All
Age
Adolescents and adults
Therapeutic alternatives
Patent information
Main patents have expired but secondary patents might remain active in some jurisdictions. For more
information on specific patents and license status for developing countries visit www.MedsPal.org
Read more
about patents.
Wikipedia
DrugBank
Expert Committee recommendation
The Committee acknowledged that insulin is a life-saving essential medicine
for which a compelling public health need exists. Yet despite being available for
almost 100 years, achieving reliable, equitable and affordable access to insulin
remains a public health challenge in many countries.
The Committee did not recommend the addition of insulin analogues
to the EML, reiterating the conclusion of the 2017 Committee, that although
the available evidence for long-acting insulin analogues shows some efficacy
advantages and reduced hypoglycaemia compared to human insulin, the
price differential that exists between analogue and human insulin remains
disproportionately high in most settings.
The Committee remained concerned about the ongoing problems of
access and affordability of insulin worldwide, despite human insulin not being
patented. The Committee noted the long-standing domination of the insulin
market by three manufacturers, limiting broader competition and slowing the
entry of biosimilars to the market.
Recognizing the complexities of these problems and the need for a
wider understanding of the insulin market and access to insulin, the Committee
recommended WHO coordinate a series of actions to address the issues of
insulin access and affordability. In the absence of other coordinated actions, the
Committee considered that the inclusion of insulin analogues for adults on the
EML would be inadequate to address the underlying issues of poor access and
affordability of insulins more generally.
The Committee recommended that a WHO-led approach should be
multi-factorial and multi-disciplinary and should include:
■ establishment of an independent WHO technical working group on
access to insulin;
■ consultation with Member States and other stakeholders to identify/
clarify barriers to access at country level;
■ strategies to address current regulatory barriers for biosimilar
insulins, such as the expansion of the WHO Prequalification
Programme;
■ development of a comprehensive approach to address insulin prices,
including mechanisms for pooled procurement;
■ identification of evidence and research gaps regarding insulin use
and supply, including setting-specific differences in clinical practice
and health systems (e.g. food insecurity, displaced populations,
emergencies).
The Committee would welcome a report that comprehensively describes
the actions that are undertaken by WHO over the next biennium and an
application that reviews in-depth the current challenges for optimal global access
and the role of insulin analogues in children.
Background
The application proposed the inclusion of long-acting insulin analogues (insulin detemir, insulin glargine, insulin degludec, including biosimilars) on the core list of the EML for treatment of patients with type 1 diabetes.
Human insulin has been included on the EML since the first list in 1977 (1).
In 1985, the WHO Expert Committee on the Selection and Use of Essential
Medicines approved the inclusion of isophane neutral protamine Hagedorn
(NPH) insulin (2).
Since 1996, different insulin analogues, altered forms of human insulins,
have been introduced on markets worldwide. In recent years, additional
comparative evidence on biosimilars and reference medications in terms of
efficacy and safety became available.
In 2017, at the 21st meeting of the Expert Committee of the WHO EML,
an application for the inclusion of long-acting analogues to the EML was rejected
due to the limited magnitude of the benefits of analogues over human insulin in
terms of reduced glycated haemoglobin and reduced hypoglycaemia as compared
to the large difference in price between analogues and human insulin (3).
Since that time, additional evidence has become available encompassing
both effectiveness and increasing affordability of analogues.
Public health relevance
Diabetes mellitus has an increasing worldwide prevalence. If current trends
continue, it is estimated that 642 adults will be living with diabetes by 2040 (4).
The incidence of type 1 diabetes mellitus (T1DM) accounts for a small proportion
of all diabetes (range: 5–10%) (5).
All people living with type 1 diabetes have an absolute need for insulin
for survival. Insulin is also required by a subset of patients with type 2 diabetes
(6). Lack of access to affordable insulin is a problem globally and contributes to
the complications of untreated or sub-optimally treated diabetes and premature
deaths (7).
Benefits
The application presented the findings of a network meta-analysis (NMA) to
evaluate the comparative effectiveness and safety of long- or intermediate-acting
insulin versus biosimilar insulins in patients with T1DM, updating the results of
a previous systematic review.
The review compared basal regimens and categorizes treatments as per
class of basal insulin (i.e. intermediate acting, long-acting and ultra-long-acting),
and specific type of basal insulin, including insulin origin and insulin frequency.
The analyses were adjusted for bolus regimen.
Sixty-eight primary studies (8–75) (and 12 companion reports) involving
15 150 patients with average age ranging from 23 to 54 years were included.
Sixty-two (91%) studies were randomized controlled trials (RCTs) and the
majority had an unclear/high risk of bias on random sequence generation,
allocation concealment, selective reporting, and ‘other’ bias (e.g. funding bias).
Details of the included studies are available in Appendix File 1 of the application
at: https://www.who.int/selection_medicines/committees/expert/22/applications/
s18.5_insulin-analogues.pdf?ua=1.
Primary efficacy outcomes of the network meta-analysis were A1c and
fasting plasma glucose. Secondary efficacy outcomes were mortality, any (total)
vascular complication, microvascular complications, macrovascular complications
and quality of life.
A1c
A basal insulin class NMA was conducted including 26 RCTs and 9241 patients
and three treatment nodes (long-acting, intermediate-acting and ultra-longacting biosimilar). Long-acting insulin was statistically superior to intermediateacting insulin (mean difference MD −0.14, 95%CI −0.21 to −0.07).
A specific type of insulin NMA was conducted on the A1c outcome
including 34 RCTs and 11 894 patients and nine treatment nodes. Across the 36
treatment comparisons, the following 11 showed statistically significant results:
– Intermediate-acting (human) insulin administered four times
a day was inferior to intermediate-acting (animal and human)
insulin administered twice a day (mean difference MD 0.31,
95% CI 0.05 to 0.57).
– Intermediate-acting (human) insulin administered qid was
inferior to intermediate-acting (human) insulin administered bid
(MD 0.43, 95%CI 0.23 to 0.63).
– Intermediate-acting (human) insulin administered qid was
inferior to intermediate-acting (human) insulin administered
once daily (od) (MD 0.32, 95%CI 0.10 to 0.53).
– Long-acting (biosimilar) insulin administered od was superior
to intermediate-acting (human) insulin administered qid
(MD −0.46, 95%CI −0.67 to −0.24).
– Long-acting (human) insulin administered bid was superior
to intermediate-acting (human) insulin administered qid
(MD −0.49, 95%CI −0.70 to −0.29).
– Long-acting (human) insulin administered bid was superior
to intermediate-acting (human) insulin administered od
(MD −0.18, 95%CI −0.30 to −0.06).
– Long-acting (human) insulin administered od was superior to
intermediate-acting (animal and human) insulin administered
bid (MD −0.19, 95%CI −0.37 to −0.01).
– Long-acting (human) insulin administered od was superior to
intermediate-acting (animal) insulin administered bid (MD
−1.27, 95%CI −2.54 to −0.01).
– Long-acting (human) insulin administered od was superior
to intermediate-acting (human) insulin administered qid
(MD −0.50, 95%CI −0.69 to −0.31).
– Long-acting (human) insulin administered od was superior
to intermediate-acting (human) insulin administered od
(MD −0.18, 95%CI −0.29 to −0.08).
– Ultra-long-acting (biosimilar) insulin administered od was
superior to intermediate-acting (human) insulin administered qid
(MD −0.44, 95%CI −0.64 to −0.23).
A sensitivity analysis to examine the impact of imputing missing standard
deviations on the results resulted in the exclusion of seven trials. The pairwise
treatment comparisons above were no longer statistically significant when the
seven trials were excluded.
When meta-regression analyses were conducted for follow-up duration,
A1c level (mild: <8%, severe: ≥8%); proportion of women; duration of diabetes;
and risk of bias associated with random sequence generation and allocation
concealment, none of the results remained statistically significant.
Statistically significant results were shown for meta-regression analyses on:
– bolus type (rapid vs short): long-acting (human) insulin
administered od was superior to intermediate-acting (animal)
insulin administered bid (MD −1.27, 95%CI −2.54 to −0.001);
– study design (parallel or crossover trials): long-acting (human)
insulin administered bid was superior to intermediate-acting
(animal) insulin administered bid (MD −1.27, 95%CI −2.53 to
−0.0007);
– baseline A1c: intermediate-acting (animal and human) insulin
administered bid was superior to intermediate-acting (animal)
insulin administered bid (MD −1.32, 95%CI −2.63 to −0.02);
– age: long-acting (human) insulin administered bid, was superior
to intermediate-acting (animal) insulin administered bid (MD
−1.31, 95%CI −2.58 to −0.04) and long-acting (human) insulin
administered od was superior to intermediate-acting (animal)
insulin administered bid (MD −1.28, 95%CI −2.54 to −0.007).
Fasting plasma glucose
A basal insulin class NMA was conducted on the fasting plasma glucose outcome
including 21 RCTs, 7685 patients, and three treatment nodes. Long-acting insulin
was statistically superior to intermediate-acting insulin (MD −1.03, 95%CI
−1.33 to −0.73) and ultra-long-acting insulin was superior to intermediate-acting
insulin (MD −1.45, 95%CI −2.12 to −0.79).
A specific type of insulin NMA was conducted on the fasting plasma
glucose outcome including 28 RCTs, 9773 patients, and eight treatment nodes.
Across the 28 treatment comparisons, the following nine showed statistically
significant results:
– Long-acting (biosimilar) insulin administered od was superior
to intermediate-acting (human) insulin administered bid
(MD −1.07, 95%CI −1.98 to −0.15).
– Long-acting (human) insulin administered bid was superior
to intermediate-acting (human) insulin administered bid
(MD −0.82, 95%CI −1.21 to −0.43).
– Long-acting (human) insulin administered od was superior
to intermediate-acting (human) insulin administered bid
(MD −1.26, 95%CI −1.66 to −0.85).
– Long-acting (human) insulin administered od was superior
to intermediate-acting (human) insulin administered od
(MD −1.15, 95%CI −1.82 to −0.49).
– Long-acting (human) insulin administered od was superior to
long-acting (human) bid (MD −0.43, 95%CI −0.82 to −0.05).
– Ultra-long-acting (biosimilar) insulin administered od was
superior to intermediate-acting (human) insulin administered qid
(MD −1.20, 95%CI −2.31 to −0.09).
– Ultra-long-acting (biosimilar) insulin administered od was
superior to intermediate-acting (human) bid (MD −1.55, 95%CI
−2.24 to −0.87).
– Ultra-long-acting (biosimilar) insulin administered od was
superior to intermediate-acting (human) insulin administered od
(MD −1.45, 95%CI −2.34 to −0.56).
– Ultra-long-acting (biosimilar) insulin administered od was
superior to long-acting (human) insulin administered bid
(MD −0.73, 95%CI −1.38 to −0.08).
Mortality
A NMA was not possible for all-cause mortality for basal insulin classes. Two
pairwise meta-analyses were possible for long-acting versus intermediate-acting
insulin (four RCTs, 1682 patients), as well as ultra-long-acting versus long-acting
insulin (two RCTs, 1540 patients). None of the results were statistically significant.
A NMA was not possible for all-cause mortality for specific types of
insulin. Three pairwise meta-analyses were possible comparing long-acting
(human) insulin administered bid versus intermediate-acting (human) insulin
administered bid (two RCTs, 653 patients), long-acting (human) insulin
administered od versus long-acting (biosimilar) insulin administered od (two
RCTs, 1093 patients) and long-acting (human) insulin administered od versus
ultra-long-acting (biosimilar) insulin administered od (two RCTs, 1540 patients).
None of the results were statistically significant.
Any (total) vascular complication
A basal insulin class NMA was conducted on any vascular complication,
including 11 RCTs and 4709 patients. Across the three treatment comparisons,
none were statistically significant.
A specific type of insulin NMA was conducted on any vascular
complication including 13 RCTs and 5589 patients. Across the 10 treatment
comparisons, none were statistically significant.
Microvascular complications
A basal insulin class NMA was conducted to compare long-acting, intermediateacting and ultra-long acting insulins on microvascular complications including
eight RCTs and 3131 patients. The transitivity assumption was upheld but
inconsistency could not be assessed since there were no closed loops in the
network meta-analysis diagram. Across the three treatment comparisons, none
were statistically significant.
A specific type of insulin NMA was conducted on microvascular
complications including 10 RCTs and 4011 patients. Across the 10 treatment
comparisons, none were statistically significant.
Macrovascular complications
For basal insulin classes, a NMA was not possible for macrovascular
complications. Two pairwise meta-analyses were possible; long-acting insulin
versus intermediate-acting insulin (three RCTs, 998 patients) and ultra-longacting biosimilar insulin versus long-acting insulin (three RCTs, 2098 patients).
The results of pairwise treatment comparisons were not statistically significant.
For specific types of insulin, a NMA was not possible for macrovascular
complications. Two pairwise meta-analyses were possible for long-acting
(human) insulin administered bid versus intermediate-acting (human) insulin
administered bid (four RCTs, 1258 patients) and long-acting (human) insulin
administered od versus ultra-long-acting (biosimilar) od (two RCTs, 1540
patients). The results were not statistically significant.
Quality of life
A NMA or pairwise meta-analyses were not possible for health-related quality
of life for basal insulin classes or specific types of insulin. One study including
517 patients reported total quality of life and long-acting (human) insulin
administered od was not statistically significant compared with intermediateacting (human) insulin administered bid. The same study reported general quality
of life and long-acting (human) insulin administered od was not statistically
significant compared with intermediate-acting (human) insulin administered
bid. With respect to basal insulin classes, similar results were observed when
long-acting insulin was compared to intermediate-acting insulin.
Harms
Weight change
A basal insulin class NMA was conducted including 16 RCTs, 6822 patients,
and three treatment nodes. Long-acting insulin was statistically superior to
intermediate-acting insulin (MD −0.70, 95%CI −1.07 to −0.33).
A specific type of insulin NMA was conducted including 20 RCTs,
8335 patients, and seven treatment nodes. Across the 21 treatment comparisons,
the following four showed statistically significant results:
– Long-acting (human) insulin administered bid was superior
to intermediate-acting (human) insulin administered bid
(MD −0.85, 95%CI −1.24 to −0.46).
– Long-acting (human) insulin administered bid was superior
to intermediate-acting (human) insulin administered od
(MD −1.18, 95%CI −2.13 to −0.24).
– Long-acting (human) insulin administered bid was superior to
long-acting (biosimilar) insulin administered od (MD −0.96,
95%CI −1.91 to −0.01).
– Long-acting (human) insulin administered bid was superior
to ultra-long-acting (biosimilar) insulin administered od
(MD −0.69, 95%CI −1.32 to −0.06).
All-cause hypoglycaemia (defined differently across RCTs)
A basal insulin class NMA was conducted including 17 RCTs and 5949 patients.
Across the three treatment comparisons, none were statistically significant.
A specific type of insulin NMA was conducted including 22 RCTs
and 6917 patients. Across the 21 treatment comparisons, none were statistically
significant.
Major or serious hypoglycaemia (defined differently across RCTs)
A basal insulin class NMA was conducted including 19 RCTs, 7324 patients,
and three treatment nodes. Long-acting insulin was statistically superior to
intermediate-acting insulin (odds ratio OR 0.63, 95%CI 0.51 to 0.76).
A specific type of insulin NMA was conducted including 25 RCTs and
9300 patients. Across the 21 treatment comparisons, the following four showed
statistically significant results:
– Long-acting (biosimilar) insulin administered od was superior to
intermediate-acting (human) insulin administered bid (OR 0.48,
95%CI 0.24 to 0.97).
– Long-acting (human) insulin administered bid was superior to
intermediate-acting (human) insulin administered bid (OR 0.69,
95%CI 0.54 to 0.88).
– Long-acting (human) insulin administered od was superior to
intermediate-acting (human) insulin administered bid (OR 0.53,
95%CI 0.39 to 0.72).
– Long-acting (human) insulin administered od was superior to
intermediate-acting (human) insulin administered od (OR 0.60,
95%CI 0.42 to 0.86).
Minor or mild hypoglycaemia
For basal insulin classes, a NMA was not possible. One pairwise meta-analysis
was possible for long-acting versus intermediate-acting insulin (eight RCTs,
2949 patients) and the results were not statistically significant.
A specific type of insulin NMA was conducted including 11 RCTs
and 3926 patients. Across the 15 treatment comparisons, none were statistically
significant.
Nocturnal hypoglycaemia (defined differently across RCTs)
A basal insulin class NMA was conducted including 16 RCTs, 6669 patients,
and three treatment nodes. Long-acting insulin was statistically superior to
intermediate-acting insulin (OR 0.71, 95%CI 0.57 to 0.89) and ultra-long-acting
biosimilar insulin was statistically superior to intermediate-acting insulin (OR
0.60, 95%CI 0.42 to 0.86).
A specific type of insulin NMA was conducted including 19 RCTs and
7564 patients. Across the 15 treatment comparisons, the following two showed
statistically significant results:
– Intermediate-acting (human) insulin administered bid was
inferior to ultra-long-acting (biosimilar) insulin administered od
(OR 1.58, 95%CI 1.11 to 2.25).
– Long-acting (human) insulin administered bid was superior to
intermediate-acting (human) insulin administered bid (OR 0.59,
95%CI 0.44 to 0.79).
Incident cancers
For basal insulin classes, a NMA was not possible. One pairwise meta-analysis
was possible for long-acting versus intermediate-acting insulin (three RCTs,
1651 patients) and the results were not statistically significant.
For specific types of insulin, a NMA was not possible. One pairwise metaanalysis was possible (two RCTs and 1204 patients), which compared long-acting
(human) insulin administered od versus intermediate-acting (human) insulin
administered bid. The results were not statistically significant.
Any (total) adverse events, serious adverse events, and dropouts due to adverse events
For basal insulin classes, NMAs were conducted on any adverse events including
16 RCTs and 5367 patients, on serious adverse events including 20 RCTs and
6840 patients, and on withdrawals due to adverse events including 14 RCTs and
5440 patients. Across the three treatment comparisons in each NMA, none were
statistically significant.
For specific types of insulin, NMAs were conducted on any adverse
events including 22 RCTs and 6830 patients, on serious adverse events including
26 RCTs and 8989 patients, and on withdrawals due to adverse events including
21 RCTs and 7795 patients. Across the 15 treatment comparisons in each NMA,
none were statistically significant.
Additional evidence
The current application does not include data on long-acting insulin analogue
use in children. Long-acting insulin analogues have been investigated extensively
in the paediatric age-group in low- and high-resource settings and were found
to be safe and effective (76–80). They are approved in children from age two
years (glargine and detemir) or one year (degludec) (81). Long-acting analogues
have also been successfully used in infants and have shown positive effects on
glucose control and on hypoglycaemia. However, the evidence is based on case
reports (82, 83).
Cost / cost effectiveness
Ten cost-effectiveness analyses reported in three studies compared long-acting
insulin detemir once a day with intermediate-acting insulin NPH once a day
(72, 73, 75). Two studies (72, 75) found that detemir was less costly and more
effective, while the third (73) showed that detemir was more costly but also
more effective than NPH. Two cost-effectiveness analyses reported in a single
study compared long-acting insulin detemir once a day with long-acting insulin
glargine once a day (74). This study demonstrated that detemir is more costeffective than glargine. Finally, a single cost-effectiveness analysis in a single
study compared ultra-long-acting biosimilar insulin degludec once a day with
long-acting insulin glargine once a day (71). Degludec was shown to be the more
cost-effective treatment in comparison to glargine.
WHO guidelines
The WHO 2018 Guidelines on second- and third-line medicines and type of insulin
for the control of blood glucose levels in non-pregnant adults with diabetes mellitus
(84) make the following recommendations regarding the use of insulin:
– Use human insulin (short-acting regular human insulin and
intermediate-acting human insulin (NPH insulin)) to manage
blood glucose in adults with type 1 diabetes and in adults with type
2 diabetes for whom insulin is indicated (strong recommendation,
low quality evidence).
– Consider long-acting insulin analogues to manage blood glucose
in adults with type 1 or type 2 diabetes who have frequent severe
hypoglycaemia with human insulin (weak recommendation,
moderate quality evidence for severe hypoglycaemia).
Recommendations from the 2018 WHO guidelines targeting type 1
diabetes were based on evidence from systematic reviews of randomized
controlled trials (85–87).
For patients with type 1 diabetes, the mean difference in HbA1c level
between short-acting insulin analogues and regular human insulin was −0.15%
(95%CI −0.20% to −0.10%) (low quality evidence). The difference in HbA1c level
in patients treated with short-acting insulin analogues compared with those
treated with regular human insulin was not considered clinically meaningful by
the guidelines development group. Long-acting insulin analogues and human
NPH insulin had similar effects on HbA1c level (moderate quality evidence).
Long-acting insulin analogues reduced risk for severe hypoglycaemia, but
only the reduction with detemir was statistically significant (moderate quality
evidence). The guideline panel concluded that the relatively modest overall
benefit from insulin analogues was outweighed by the large price difference
between human insulin and insulin analogues. Thus, the panel considered use
of long-acting detemir and glargine insulin analogues as alternatives to human
insulin only in specific circumstances, such as unexplained and frequent severe
hypoglycaemic events.
Availability
Three pharmaceutical companies are solely responsible for the supply of almost
all insulin on markets worldwide. Despite being available for almost 100 years,
achieving reliable, equitable and affordable access to insulin, human or analogue,
remains a public health challenge in many countries (88). The Committee
recognized the need for a wider understanding of the complexities of access to
insulin and the current insulin market and recommended WHO to prioritize
the coordination of a series of actions to address the issues of insulin access
and affordability
Other considerations
Comments on the application were received from the WHO Department of
Management of NCDs, Disability, Violence and Injury Prevention. The technical
unit advised that it did not support the application to add long-acting insulin
analogues (including biosimilars) to the EML, nor was the application developed
in consultation with the technical department.
The review found long-acting insulin analogues to be superior to intermediate
acting insulin with regard to major or serious hypoglycaemia, which may
represent an advantage particularly in settings where food security is not reliable.
Glucagon, used in the management of severe hypoglycaemia, has very limited
availability in many low-resource settings (89). Thus, the lower incidence of
major or serious hypoglycaemia associated with the use of (ultra) long-acting
insulin analogues may offer further advantages in such settings.
The Committee acknowledged and noted the comments received in
relation to this application from organizations and individuals expressing
concern about the potential inclusion of insulin analogues on the Model List and
associated consequences.
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