Download New Developments in Insulin Therapy for Type 2 Diabetes

New Developments in Insulin Therapy for
Type 2 Diabetes
Christopher Sorli, MD, FACE
Department of Diabetes, Endocrinology and Metabolism, Billings Clinic, Billings, Mont.
ABSTRACT
Insulin has classically been considered a treatment of last resort for individuals with type 2 diabetes,
delayed until all other efforts by the patient and healthcare provider have failed. Recent treatment guidelines
recommend the use of insulin, in particular basal insulin, as part of a treatment regimen earlier in the disease
process. Many patients are reticent about initiating insulin, so therapies that allow insulin treatment to be
more tailored to individual needs are likely to result in greater acceptance and patient adherence with
therapy. To meet this need, a range of insulin products are in development that aim to increase absorption
rate or prolong the duration of action, reduce peak variability and weight gain associated with insulin
treatment, and offer alternative delivery methods. This review describes insulin products in clinical
development, new combination therapies, and new devices for insulin delivery.
Ó 2014 Elsevier Inc. All rights reserved. The American Journal of Medicine (2014) 127, S39-S48
KEYWORDS: Basal insulin; Insulin; Type 2 diabetes
Exogenous insulin is well established as the primary and
lifesaving therapy for type 1 diabetes. Individuals with type
2 diabetes initially are treated with lifestyle changes
including diet and exercise,1-3 but treatment intensification
because of declining beta-cell function usually is required
and blood glucose may become inadequately controlled
with oral glucose-lowering treatments or incretin-based
therapies only. At this stage, supplementary insulin therapy typically is added, but insulin has classically been
considered the final treatment option for individuals with
type 2 diabetes.1-3
As treatment guidelines and insulin products are refined,
however, it is increasingly being recognized that insulin
may be used at an earlier stage in the management of type 2
Funding: The publication of this manuscript was funded by Novo
Nordisk Inc.
Conflict of Interest: CS is a member speaker bureau for AstraZeneca,
Novo Nordisk, Eli Lilly, and Bristol Meyers Squibb; has received research
support from Eli Lilly, Novo Nordisk, Sanofi, MannKind, and GI Dynamics; and is on the advisory board for GI Dynamics and Novo Nordisk.
Authorship: The author takes full responsibility for the content of this
manuscript. Writing support was provided by Watermeadow Medical.
Requests for reprints should be addressed to Christopher Sorli, MD,
FACE, Department of Diabetes, Endocrinology and Metabolism, Billings
Clinic, Billings, MT 59101.
E-mail address: [email protected]
0002-9343/$ -see front matter Ó 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.amjmed.2014.07.006
diabetes. Recent treatment guidelines emphasize individualized therapy, acknowledging the difficulties associated
with lifestyle therapy and the progressive nature of the
disease. Some patients are recommended to include insulin,
in particular basal insulin, as a component of treatment
earlier in the disease process. In this way, the role of basal
insulin changes from one of damage control in an inevitably
progressive disease to one of preventative care, with the
ability to modify the disease process in a positive way.4
Because many patients are reluctant to initiate multiple
daily injections of insulin, insulin initiation often involves
basal-only therapy in conjunction with existing oral glucoselowering drugs. Used as supplementary therapy, insulin can
rest beta-cells and facilitate recovery of the prandial
response; however, early intensive therapy may offer advantages in beta-cell preservation in type 2 diabetes.5
Patient-friendly, effective, and safe therapies that allow insulin treatment to be fully tailored to individual needs will
significantly influence adherence to therapy. This review
describes insulin products in clinical development, new
combination therapies, and new devices for insulin delivery.
NEW BASAL INSULIN PRODUCTS
The currently available basal insulin analogs, insulin glargine (Lantus; Sanofi, Paris, France) and insulin detemir
(Levemir; Novo Nordisk Inc, Plainsboro, NJ), offer an
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The American Journal of Medicine, Vol 127, No 10A, October 2014
improvement over neutral protamine Hagedorn insulin in
terms of duration of action and reduced peak effect.6-8
However, they still demonstrate suboptimal/nonideal pharmacokinetic and pharmacodynamic properties.9 A basal
insulin ideally will provide a continuous and flat glucoselowering effect over 24 hours in all patients, with low
day-to-day variability (reducing the risk of hypoglycemia)
and once-daily dosing for all. Both insulin glargine and
insulin detemir need to be injected at the same time each
day; this can make adherence difficult for patients who have
varying daily schedules. As discussed by Tibaldi,10 insulin
degludec (Tresiba; Novo Nordisk Inc) is a novel basal insulin comprising recombinant DesB30 human insulin acylated at the LysB29 residue with a hexadecandioyl-g-L-Glu
side-chain that has a unique mode of protraction.11,12 The
pharmacokinetic/pharmacodynamic profile of insulin
degludec confers reduced variability at similar efficacy to
insulin glargine, with a lower risk of nocturnal hypoglycemia and the ability to dose more flexibly.13-18 Insulin
degludec is approved for use in several regions, including
Europe, Japan, and Mexico, and regulatory filings in several
other countries have been submitted. Approval in the United
States is conditional on a satisfactory outcome in a dedicated
cardiovascular safety trial.19
The molecular structure of insulin degludec permits the
production of a co-formulation containing 70% insulin
degludec and 30% insulin aspart (Ryzodeg; Novo Nordisk
Inc), which has been approved in Europe, Japan, and Mexico,
with product availability anticipated during 2014. In
combining the long duration of action of insulin degludec
with the rapid-acting insulin analog, insulin aspart
(NovoRapid/NovoLog; Novo Nordisk Inc), this product aims
to provide 24 hours of basal insulin coverage with additional
post-prandial blood glucose control for 1 meal per day.
Several new insulin products are in clinical development.
PEGYLATED INSULIN LISPRO (LY2605541)
Exogenously administered insulin is prone to glomerular
filtration and therefore to significant renal clearance.
PEGylated insulin lispro (PEG-lispro; Eli Lilly and Company, Indianapolis, Ind) is a novel basal insulin comprising
lispro covalently bound to a 20 kDa polyethylene glycol
chain (PEG) at lysine B28, resulting in a large hydrodynamic size. PEGylation appears to alter the tissue distribution of this insulin, delay absorption, and reduce renal
clearance as incorporation of water molecules into hydrophilic structures increases the effective size of the molecule
beyond the filtration potential of the kidney. These effects
increase the duration of action to >36 hours.20,21
Endogenous insulin is secreted into the portal vein and
travels directly to the liver, where approximately 80% is
extracted.22 Exogenous insulin is absorbed into the systemic
circulation, leading to high concentrations in peripheral
tissue, which may account for weight gain associated with
insulin treatment.23 It is proposed that the large size of PEGlispro may reduce transport into peripheral tissue, such as
adipose tissue.24 Moore et al25 have postulated that the
fenestrated sinusoidal endothelium of the liver may allow
preferential transport of PEG-lispro into the liver relative to
peripheral tissues, and a clamp study in dogs suggested that
PEG-lispro had a preferential hepatic versus peripheral
effect on glucose metabolism.
Clamp studies have shown that PEG-lispro has a longer
duration of action and less variability compared with insulin
glargine.21,26 In phase II trials, once-daily PEG-lispro
(administered in the morning) provided similar blood
glucose levels to insulin glargine, with less variability. In
one study, the overall percentage of patients with type 2
diabetes reporting nocturnal hypoglycemia was similar with
PEG-lispro and insulin glargine (25.6% vs 34.4%, P ¼
.127); however, there was a rate reduction of 48% in favor
of PEG-lispro when data were adjusted for baseline differences (P ¼ .021).24 Furthermore, patients receiving PEGlispro lost weight (mean [standard deviation {SD}] weight
loss, 0.6 [0.2] kg, P ¼ .007), whereas patients receiving
insulin glargine gained weight (mean [SD] weight gain, 0.3
[0.2] kg, P ¼ .662; treatment difference: 0.8 kg, P ¼ .001).
In a phase II study in patients with type 1 diabetes, the
overall hypoglycemia rate was 12% higher with PEG-lispro
than insulin glargine (mean [SD] events/patient/30-day
period: 8.74 [7.70] vs 7.36 [6.80]; P ¼ .037).27 However,
the nocturnal hypoglycemia rate was 25% lower with PEGlispro in this study (0.88 [1.22] vs 1.13 [1.42] events/patient/
30-day period; P ¼ .012). Consistent with the study in patients with type 2 diabetes, PEG-lispro was associated with a
mean weight loss of 1.20 kg (P < .0001), whereas insulin
glargine was associated with a mean weight gain of 0.69 kg
(P ¼ .0007) (least-squares mean difference, e1.89 kg) (P <
.0001).27 In both studies, enzyme levels used for liver
function tests (alanine aminotransferase and aspartate
aminotransferase) were increased in the PEG-lispro versus
the insulin glargine treatment groups.24,27
Larger phase III clinical trials with PEG-lispro are
ongoing, including a randomized clinical trial of PEG-lispro
used in basalebolus therapy in type 2 diabetes (NCT
0146898728), which was completed in August 2013, and
publication of data is awaited.
HIGH-DOSE FORMULATIONS
Many patients with type 2 diabetes are obese and may
display insulin resistance, requiring high doses of insulin.
Increasing the insulin concentration reduces the injection
volume and potentially reduces the number of injections
needed to deliver the required dose. However, changing the
concentration may alter the pharmacodynamic profile
because the surface area of the depot in contact with the
interstitial fluid is reduced, which may slow absorption. A
500 U/mL formulation of human insulin was shown to have
significantly delayed absorption in pigs when compared
with a 100 U/mL formulation.29
Clinical studies of a 300 U/mL formulation of insulin
glargine (U300) by Sanofi are under way, and phase I and II
Sorli
Insulin Developments for Type 2 Diabetes
trials are complete. In a single-dose clamp study the U300
formulation had a flatter profile, with less fluctuation in
individual glucose infusion rates, than U100 insulin glargine, and full blood glucose control was maintained until the
end of the clamp (36 hours).30 Exposure and bioactivity
after injection of U300 were reduced approximately 40%
compared with exposure and bioactivity after administration
of the same amount (0.4 U/kg) of insulin glargine U100.31
Likewise, in a study conducted at steady state, the U300
insulin glargine formulation had a flatter profile and longer
duration of action compared with the U100 insulin glargine
formulation.32
The first insulin glargine U300 phase III results in
patients with type 2 diabetes using basalebolus therapy
were recently presented (EDITION I [NCT0149908233]
and EDITION II [NCT0149909534]). In EDITION I, insulin glargine U300 was noninferior in terms of glycated
hemoglobin (HbA1c) reduction and associated with a
21% reduction in the incidence rate of confirmed (>70
mg/dL) and severe nocturnal hypoglycemia from months
3 to 6 compared with insulin glargine U100.35 EDITION
II showed similar reductions in HbA1c (e0.57% and
0.56%) with insulin glargine U300 versus insulin
glargine U100, but the rate of severe hypoglycemia
was significantly 23% lower with U300 from months
3 to 6.36 Additional phase III studies (EDITION III
[NCT0167622037]) in patients with type 2 diabetes
comparing insulin glargine U300 with U100 are ongoing,
whereas other phase III studies are currently recruiting
patients (EDITION I Japan [NCT0168912938] and EDITION IV [NCT0168326639]).
A 400 U/mL formulation of recombinant human insulin
(BIOD-530; Biodel Inc, Danbury, Conn) is in development
for patients with insulin resistance. BIOD-530 has a faster
rate of absorption and onset of action compared with 500
U/mL human insulin.40 The formulation contains disodium
ethylenediaminetetraacetic acid, as well as citrate and
magnesium sulfate, which have been shown in multiple
clinical studies to mitigate injection site pain associated with
ethylenediaminetetraacetic acid.
Insulin degludec is manufactured in a high-dose
formulation (200 U/mL), as well as the 100 U/mL
formulation, but this insulin is unique in that the 2 formulations do not show different pharmacodynamic profiles.41 Insulin degludec forms soluble multi-hexamers on
subcutaneous injection, resulting in a depot from which
monomers are slowly and continuously absorbed to provide an ultra-long action profile in which the monomer
release rate is the limiting factor.11,42,43 A 26-week randomized, controlled trial in insulin-naïve patients with type
2 diabetes reported similar HbA1c reductions with insulin
degludec U200 compared with insulin glargine U100.44
The fasting plasma glucose reduction was slightly, but
significantly, greater with insulin degludec (e67 vs e61
mg/dL, P ¼ .02), whereas hypoglycemia occurred at lower
rates with insulin degludec versus insulin glargine (not
significant).
S41
ULTRAeRAPID-ACTING INSULINS
In contrast to basal insulins, rapid-acting insulins are
designed to be absorbed quickly over a short interval and are
taken before meals to limit postprandial hyperglycemia;
thus, they attempt to mimic the physiologic prandial insulin
response. Current rapid-acting insulin analogs (aspart, lispro, and glulisine [Apidra; Sanofi]) offer an improvement
over soluble human insulin in terms of faster onset, shorter
duration of action, and greater predictability. Faster-acting
insulin aspart is a new ultraerapid-acting formulation of
insulin aspart being developed by Novo Nordisk that has
entered phase III trials. These trials will compare fasteracting insulin aspart with insulin aspart in basalebolus
therapy in patients with type 1 diabetes (onset 1
NCT0183176545) and in basalebolus therapy plus metformin in patients with type 2 diabetes (onset 2 NC
T0181912946). A further trial will compare basalebolus
therapy with faster-acting insulin aspart with a basal-only
regimen, both with metformin (NCT0185061547) in patients with type 2 diabetes. Compared with current prandial
insulins, the faster onset of action is expected to better
mimic the immediate prandial insulin response seen in
people without diabetes.
Another ultraerapid-acting bolus insulin in development
is BIOD-123 (Biodel Inc, NCT0190889448 and NCT0
168662049), which is a formulation of recombinant human
insulin. Magnesium sulfate is added to BIOD-123 as an
excipient, accelerating absorption and reducing injection site
reactions.50 In an ongoing phase II trial, this formulation
demonstrated significantly faster absorption rates compared
with insulin lispro (NCT0168662049).
ADDITION OF HYALURONIDASE
A further approach to increasing the speed of insulin absorption is to combine it with human recombinant hyaluronidase.51 Hyaluronidase enzymes speed up the dispersion
and absorption of co-administered molecules by momentarily
breaking down the interstitial barrier. Clamp studies investigating human recombinant hyaluronidase with insulin lispro
or human insulin51 or insulin aspart, glulisine, and lispro52
showed that the addition of hyaluronidase accelerated insulin exposure, producing an ultraerapid-action profile in
healthy subjects.51,52 Data consistent with these healthy
volunteer studies also were obtained in patients with type 1
diabetes.53 Addition of hyaluronidase has been shown to
result in decreased intra-subject variability of pharmacokinetic end points.54
NEW TREATMENT COMBINATIONS: COMBINING
INSULIN AND INCRETIN THERAPY
At the time of diagnosis, beta-cell function is compromised
by up to 50% in patients with type 2 diabetes.55 Glycemic
targets may be achieved in 50% to 60% of patients with type
2 diabetes using basal insulin alone.56 For those unable to
achieve glycemic targets, further intensification is required
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to reduce post-prandial glucose levels,57,58 and prandial
insulin injections often are added to basal insulin. Although
highly efficacious, multiple daily injections of insulin therapy are associated with an increased risk of hypoglycemia,59
weight gain, and the need for frequent blood-glucose
monitoring.
The American Diabetes Association/European Association for the Study of Diabetes and American Association of
Clinical Endocrinologists position statements consider
incretin-based therapies a possible alternative to insulin
initiation after failure of lifestyle changes and metformin in
patients with type 2 diabetes,60,61 and there is increasing
interest in the use of these drugs in combination with insulin. The incretin hormone glucagon-like peptide-1 is
secreted into the circulation by intestinal cells in response to
caloric intake. Glucagon-like peptide-1 has multiple effects,
including glucose-dependent stimulation of insulin secretion
and suppression of glucagon secretion, reduced gastric
emptying, and increased satiety.62 Incretin-based therapies
include dipeptidyl peptidase-4 inhibitors, such as sitagliptin,
linagliptin, and saxagliptin, and glucagon-like peptide-1
receptor agonists, such as exenatide, liraglutide, and
lixisenatide.
Incretin-based therapies tend to augment the prandial
insulin response and induce independent mechanisms to
reduce postprandial hyperglycemia, and they have an
advantage over prandial insulin analogs in that they incur
a lower risk of hypoglycemia and are not associated with
weight gain. In the case of glucagon-like peptide-1 receptor agonists, there is typically a degree of weight loss,
and they may slow disease progression by helping to
preserve residual beta-cell function.63 Long-acting
glucagon-like peptide-1 receptor agonists have been
associated with gastrointestinal side effects, including
nausea, vomiting, and diarrhea, but the side effects typically diminish over time and can be avoided by gradual
escalation of the dose. The combination of insulin and
incretin-based therapies is an attractive option because it
is likely to increase the number of patients reaching
glycemic target compared with a glucagon-like peptide-1
receptor agonist or basal insulin alone, while having a
lower risk of hypoglycemia and weight gain than basal
insulin alone or multiple daily injections of insulin.64,65
The glucose-dependent effect of a glucagon-like peptide-1 receptor agonist is expected to augment the prandial insulin response and limit postprandial
hyperglycemia. Supplementary basal insulin also would
help to control fasting plasma glucose and rest the betacell to allow for a better post-prandial response.
CO-ADMINISTRATION OF INCRETIN AND
INSULIN THERAPY
Studies show that the combination of incretin-based
therapies with basal insulin is a viable alternative to
introducing prandial insulin injections in patients with
inadequately controlled diabetes by either therapy alone.
In addition to the benefits associated with incretin-based
therapies discussed previously, the synergistic nature of
the combination allows the administration of a lower dose
of insulin, contributing to reductions in risk of hypoglycemia and weight gain. Retrospective analyses of patients
with inadequately controlled type 2 diabetes who were
co-prescribed insulin glargine and exenatide suggest that
regardless of treatment order, long-term combined therapy with insulin glargine and exenatide reduces HbA1c
without significant weight gain or increased hypoglycemia risk.66,67 Similar outcomes have been demonstrated
in patients receiving once-daily lixisenatide as an add-on
to basal insulin.68,69 Saxagliptin as an addition to metformin and basal insulin was shown to improve HbA1c
(difference in adjusted mean HbA1c: e0.41%, P < .0001)
and post-prandial blood glucose (difference in 120minute post-prandial glucose: e23.0 mg/dL, P ¼ .0016)
at 24 weeks compared with placebo without increasing
the rate of hypoglycemia.70
Rosenstock et al71 recently published results from a
52-week study showing that the addition of insulin detemir
to liraglutide and metformin led to significant further improvements in glycemic control in patients who had failed
to reach target using liraglutide and metformin alone.
Compared with continuation on liraglutide and metformin
alone, the addition of insulin detemir significantly reduced
HbA1c (e0.51%; 95% confidence interval [CI], 0.70 to
0.31; P < .0001) and fasting plasma glucose (e1.77
mg/dL; 95% CI, e2.24 to e1.30; P < .0001) by the end of
the study. Weight loss observed during the run-in period
with liraglutide and metformin (e3.5 kg) was maintained
over 52 weeks in patients adding insulin detemir (weight
change: e0.05 kg in this period). In the control group
randomly assigned to continue on liraglutide and metformin
alone, weight decreased further over the same period
(1.02 kg, estimated treatment difference: 0.97 kg; 95%
CI, 0.04-1.91; P ¼ .04). The rate of hypoglycemia was
higher in patients adding insulin detemir than in the control
patients (0.23 events/patient-year vs 0.03 events/patientyear, respectively), but these rates are nevertheless both
low.71
The study of basal insulin plus incretin therapy recently
has been extended to investigate the feasibility of using a
glucagon-like peptide-1 receptor agonist as an alternative to
prandial insulin. One such study, of 26 weeks’ duration,
randomized patients whose type 2 diabetes remained inadequately controlled (HbA1c 7.0%) after 2 years of treatment with insulin degludec plus metformin to receive
additional once-daily liraglutide or once-daily insulin aspart
(taken with the largest meal).72 In this study, addition of
liraglutide resulted in a significantly greater improvement in
HbA1c compared with insulin aspart (estimated treatment
difference: 0.32%; 95% CI, 0.53 to 0.12; P ¼ .0024)
and an 87% reduction in the rate of total hyperglycemia
(1.00 vs 8.15 episodes/patient-y of exposure, respectively,
P < .0001). In addition, patients adding liraglutide benefited
from a mean weight loss of 2.8 kg, whereas those adding
Sorli
Insulin Developments for Type 2 Diabetes
S43
insulin aspart gained on average 0.9 kg (estimated treatment
difference: 3.8 kg; 95% CI, 4.7 to 2.8; P < .0001).72
controlled with metformin and glucagon-like peptide-1 receptor agonist therapy.
COMBINATION INSULIN/INCRETIN THERAPY:
INSULIN DEGLUDEC/LIRAGLUTIDE
INSULIN GLARGINE/LIXISENATIDE FIXED
COMBINATION
Given the promising outcomes of studies in which basal
insulin and incretin therapies have been used together,
products are now being developed in which the 2 components are combined in a single pharmaceutical formulation
for convenient administration in a single injection. One
product combining insulin degludec and liraglutide (IDegLira; Novo Nordisk Inc) contains a fixed ratio of 1 unit of
degludec and 0.036 mg of liraglutide per unit drug. Data
have been reported from a 26-week trial (DUAL I)
involving patients with type 2 diabetes, which compared
IDegLira with insulin degludec alone and liraglutide alone,
each as an addition to metformin with or without pioglitazone.73 The IDegLira combination product showed superior
HbA1c reductions compared with insulin degludec or liraglutide alone, and fasting plasma glucose reductions were
significantly greater with IDegLira than with liraglutide.
Post-prandial glucose control was significantly better with
IDegLira compared with insulin degludec alone, and similar
to that achieved with liraglutide alone.73 The risk of hypoglycemia was significantly lower with IDegLira versus insulin degludec alone (rate ratio, 0.68) but significantly
higher compared with liraglutide alone (rate ratio, 7.61)
(both P < .0001)73; however, compared with liraglutide
alone there were fewer gastrointestinal adverse events in
patients receiving IDegLira.
In a second 26-week, double-blind trial (DUAL II) in patients with inadequately controlled diabetes who were taking
basal insulin and oral antidiabetic agents, superior HbA1c
(estimated treatment difference: 1.1%, P < .0001) and
fasting plasma glucose reductions (63 mg/dL vs 47 mg/dL,
P ¼ .0019) were observed with IDegLira compared with insulin degludec. Moreover, mean 9-point glucose profiles were
significantly (P < .0001) lower with IDegLira (135.2 mg/dL)
than with insulin degludec (157 mg/dL), as was the mean
prandial increment across meals (IDegLira: 40 mg/dL vs insulin degludec: 43 mg/dL, P ¼ .026).74
These results suggest that the IDegLira combination may
result in a substantial improvement in glycemic control with
a low risk of hypoglycemia and weight gain, providing a
convenient way for patients to intensify their therapy with a
low injection frequency. A marketing authorization application for this product was submitted to the European
Medicines Agency, who have recently adopted a positive
opinion, recommending marketing authorization for IDegLira
for the treatment of adults with type 2 diabetes. Two further
trials of IDegLira are currently under way or recently
completed: NCT0161816275 (DUAL IV) is a placebocontrolled trial investigating the addition of IDegLira to
oral therapies in poorly controlled type 2 diabetes, and
NCT0167611676 (DUAL III) compares IDegLira with liraglutide or exenatide in patients with type 2 diabetes poorly
Another basal insulin/glucagon-like peptide-1 receptor
agonist fixed-dose combination product, namely, insulin
glargine/lixisenatide, is in clinical development by Sanofi. A
24-week phase II trial (NCT0147647577), which compared
this combination with insulin glargine alone and with metformin in patients with type 2 diabetes, has been completed,
but the results have not been presented. Sanofi has been
developing a combination product of insulin glargine and
lixisenatide in which each of the 2 components can be dosed
flexibly, because it may be an advantage if the dose of one
component is not “controlled” by the dose of the other.
However, because of technical difficulties, Sanofi has suspended the development of the “flex-dose” product at the
present time.
DEVELOPMENTS IN INSULIN ADMINISTRATION
For many patients, administering insulin by subcutaneous
injection seems like a daunting therapy option, and as a
result there may be procrastination over insulin initiation.
Consequently, research is being undertaken on alternative
methods for administering insulin. Oral insulin may offer a
welcome alternative by facilitating insulin initiation and
increasing patient adherence to treatment. A potential
advantage of oral insulin is that insulin absorbed via the gut
will undergo hepatic first-pass metabolism with reduced
peripheral exposure, thereby replicating the physiologic
route of insulin distribution.78 Oral insulin is particularly
indicated for the early stages of type 2 diabetes, when
slowing disease progression may be possible by providing
the pancreas with some respite. However, the reduced
bioavailability and low reproducibility that result when insulin is required to cross the gastrointestinal tract mucosa
have hampered efforts in this field.79
A liquid spray of recombinant human insulin
(Oral-lyn; Generex Biotechnology Corp, Toronto, Ontario,
Canada) is currently in phase III trials (NCT00948493,80
NCT0066885081). Delivered transbuccally using a “RapidMist” device that delivers 10 U of insulin per spray, Orallyn is rapidly absorbed (15 minutes), reaching a maximum
concentration after approximately 30 minutes and returning
to baseline after 2 hours. The large size of the micelle spray
particles (>10 mm) prevents entry into the lungs.82 Therefore, the exact mechanism of absorption is not fully elucidated, and only approximately 10% of the dose is absorbed;
rates of absorption are expected to differ in different regions
of the oral cavity.
Pre-prandial oral insulin capsules (ORMD-0801; Oramed
Pharmaceuticals Inc, Jerusalem, Israel) are being investigated. A recent pilot study showed that the addition of oral
insulin to stable insulin treatment was well tolerated in
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The American Journal of Medicine, Vol 127, No 10A, October 2014
8 patients with poorly controlled type 1 diabetes. Overall
glucose exposure was reduced by 16.6% (vs pretreatment
records) during continuous glucose monitoring.83 A small
study in healthy individuals showed an inverse correlation
between blood glucose levels and 2 doses of the oral insulin
capsule.84 In 2013, the Food and Drug Administration
(FDA) granted clearance for Oramed to proceed with phase
II trials of the drug in the United States.
INHALED INSULIN
Inhaled human insulin (rDNA origin) (Afrezza; MannKind
Corp, Valencia, Calif) is an ultraerapid-acting insulin that
uses Technosphere drug delivery technology whereby regular human insulin molecules are absorbed onto Technosphere (powder) particles as charge-masked monomers. The
particles are inhaled using breath-activated inhalers containing pre-metered unit doses of insulin and become a
liquid on contact with the neutral pH of the alveolar
epithelium. Afrezza onset of action is faster than that of
recombinant human insulin; maximum concentration is
achieved after 15 minutes, approximately 2 hours earlier
than for recombinant human insulin and approaching the
timing of physiologic prandial insulin release.85,86
Maximum post-prandial plasma glucose concentration is
approximately 40% lower with Afrezza than with recombinant human insulin.85,86
Rosenstock et al87 have published results from a study
comparing twice-daily premixed (biphasic) insulin aspart
(70% insulin aspart protamine suspension and 30% insulin aspart of rDNA origin) with prandial Afrezza
inhaled insulin plus bedtime insulin glargine. Similar
HbA1c reductions (between-group difference: 0.07%;
95% CI, e0.13 to 0.27), a reduced incidence of hypoglycemia (47.99% vs 68.88%; odds ratio, 0.417; 95% CI,
0.303-0.573; P < .0001), and less weight gain (treatment
difference: e1.6 kg; 95% CI, e2.4 to e0.7; P ¼ .0002)
were reported with Afrezza/insulin glargine than with the
premix regimen. No major safety issues were identified in
the 302 patients using Afrezza; however, an increased
incidence of cough and respiratory events was observed;
these were described as nonprogressive and unlikely to be
clinically meaningful. The pulmonary safety of Afrezza
was investigated over 2 years and compared with regular
clinical practice. No significant differences in pulmonary
function were detected between groups, but there was a
decline in function in both groups over the treatment
period.88 Transient mild cough was reported with
Afrezza, likely due to airway irritation from the powder.
Afrezza was denied US FDA approval in 2011, but
resubmission is expected.
A rapid-acting inhaled human insulin (Exubera; Pfizer,
New York, NY) has been used to treat type 1 and type 2
diabetes in adults, was withdrawn in 2007 because of
disappointing global sales. A warning was subsequently
issued to include information about lung cancer cases
observed in patients who used Exubera. Over the course
of a clinical trial, 6 of 4740 Exubera-treated patients
developed lung cancer, compared with 1 of 4292 patients
not treated with Exubera. An additional case of lung
cancer in an Exubera-treated patient was discovered after
approval of the drug by the FDA. All patients who
developed lung cancer had a history of cigarette smoking,
and there were insufficient cases to determine a causal
relationship between the use of Exubera and the development of lung cancer; however, concern over these data
led to the termination of all further development of the
drug.
PUMP THERAPY
Continuous subcutaneous insulin infusion pumps currently
are used by 20% of 25% of patients with type 1 diabetes in
the United States,89 and they offer a reduction in hypoglycemia and modest improvements in HbA1c compared with
multiple daily injections.90 Patch pumps are new-generation
insulin infusion pumps that deliver continuous insulin, with
the possibility of adding bolus mealtime doses. A middle
ground between syringe/insulin pens and a full pump system, patch pumps are smaller and, in general, easier to
operate than conventional pumps. Pump therapy can be
coupled to continuous glucose monitoring, enabling minuteby-minute adjustment of insulin dose. By improving delivery and simplifying treatment regimens for patients, patch
pumps may offer an option for those who struggle to control
their blood glucose or who have recurrent hypoglycemia
with injections of insulin analogs.
Several patch pumps are currently marketed, including
the OmniPod (Insulet Corp, Bedford, Mass) and V-Go
(Valeritas Inc, Bridgewater, NJ) (as reviewed by Ramchandani and Heptulla91). Potential drawbacks to pump
therapy include high costs, patient training requirements,
and reliability concerns.
In a 30-day study of the OmniPod system in 20 patients
with type 1 diabetes, 18 of 20 patients (90%) stated a
preference for the OmniPod over their current infusion set.
HbA1C values at day 30 were significantly lower (mean,
6.8%; range, 5.4-7.6; P < .002) than at baseline.92 In a
subsequent 1-year, proof-of-concept trial in 21 patients with
type 2 diabetes requiring insulin treatment, HbA1c level
7.0%, and severe insulin resistance, it was demonstrated
that treatment with insulin U500 via the OmniPod system
significantly reduced HbA1c by 1.23% (P < .001) and
significantly increased the percentage of time spent in the
blood glucose target range (70e180 mg/dL) by 70.75% as
assessed by continuous glucose monitoring (P < .001)
without a significant increase in hypoglycemia. At the end
of the study period, 14 of 20 patients who completed the
study elected to remain on treatment.93
The V-Go system is aimed at a type 2 diabetes population requiring basal and bolus insulin. In a retrospective
analysis of glycemic control in 23 patients who used the
V-Go system for 12 weeks, the mean patient rating of the
overall experience at 12 weeks was 9.1 (on a scale from 1 to
Sorli
Insulin Developments for Type 2 Diabetes
10, where 10 is most positive).94 Mean HbA1c decreased
from baseline (from 8.8% to 7.6%; P ¼ .005) while using
the V-Go system and increased to 8.2% 12 weeks after the
end of the trial.94
FUTURE IDEAS
The “holy grail” for treatment of advanced type 2 diabetes
requiring insulin treatment or type 1 diabetes is to create a
closed loop system, or “artificial pancreas,” that releases
insulin according to the patient’s needs, as reviewed by
Hovorka89 (Figure 1). Such a device would comprise a
continuous glucose monitoring system, an insulin pump,
and a control algorithm that facilitates the delivery of the
correct amount of insulin. Initially, these systems will be
aimed at those with recurrent hypoglycemia and children
who struggle to manage their diabetes; however, they have
the potential to benefit all patients. The Medtronic 530G
with Enlite technology system (Medtronic, Northridge,
Calif) has recently launched in the United States after FDA
approval.95 The system provides a threshold suspend
feature that will automatically stop insulin delivery when a
preset low blood glucose value is detected by the continuous
glucose monitor. More complex systems are still being tested
in vivo and are several years from clinical use. In addition,
ultraerapid-acting insulins may be better suited to closedloop systems than currently available insulins.
Several studies have investigated glucose-sensitive insulin, which uses a gel-based system to control the release of
insulin. The preparation contains glucose oxidase, catalase,
Figure 1 Depiction of a closed-loop insulin delivery system.
A sensor (black rectangle) identifies and transmits interstitial
glucose data to a controller (red box), which runs a control
algorithm and interacts with the user. An insulin pump (blue
box) subcutaneously delivers a rapid-acting insulin analogue.
Insulin delivery is modulated in real-time by the control algorithm. Communication between system components is wireless.
Reproduced with permission from Hovorka.89
S45
and insulin.96 Glucose diffuses into the gel and is converted
to gluconic acid, leading to swelling of the gel and the
release of insulin. An in vivo rodent model study showed
that the gel-based insulin delivery provided glucose control
and was well tolerated; however, a mechanism for refill is
required for future models.97
CONCLUSIONS
Because of the increasing prevalence of type 2 diabetes and
the earlier age of onset, the need to intensify treatment to
manage glycemia is expanding. New treatment guidelines
for type 2 diabetes encourage an appreciation of its variable
and progressive nature, the specific role of each drug, and
the patient and disease factors that drive clinical decision
making. These guidelines advocate individualized, patientcentered care that is effective in the context of the patient’s life. New user-friendly therapies are sought that can
easily be individualized to treatment goals, enabling patients
to reach glycemic target with a low risk of hypoglycemia
and, ideally, without weight gain. There are several promising new insulin products and technologies in development
that aim to meet such demands.
ACKNOWLEDGMENTS
The author thanks Watermeadow Medical for writing and
editorial assistance, funded by Novo Nordisk.
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