Quote of the Day
“Everyone knows it requires brains to
live long with diabetes, but to use insulin successfully requires more brains”
Elliott P. Joslin, MD
By Dr. GB Bolli, MD and Dr. LF Meneghini, MD, MB
ADA Conference 2012
Basal Insulins
Insulin Degludec
·
New ultra-long-acting insulin analogue
·
The degludec molecule differs from human
insulin in that the amino acid residue threonine in position B30 has been
removed and the lysine in position B29 has been coupled with a C16 fatty
di-acid (hexadecanedioic acid) via a spacer of glutamic acid
·
This allows for rapid formation of multihexamers
in the subcutaneous space in the presence of zinc
·
This multihexamer depot slowly dissociates into
monomers that are absorbed into the circulation allowing for the long duration
of action
·
Pharmacokinetic data reveal that degludec has a
flat action profile at steady state with a terminal half-life of 24 hours and
duration of action of at least 40 hours
·
In type 1 DM, degludec contains 6nmol insulin in
1 unit (like glargine); detemir contains 24 nmol insulin in 1 unit
·
Phase III studies have been completed in T1DM
and T2DM patients
·
Advantages
o
Sustained, > 24 h effect
o
Low variability in SC absorption
o
Low rate of hypoglycemia
·
Disadvantages
o
More pharmacodynamics information in clinical
situations
o
How much hypoglycemia in T1DM and T2DM
o
How to titrate dose?
o
Not yet approved in Canada
LY2605541
·
Novel basal insulin analogue that has a
prolonged duration of action due to slowing of absorption from the subcutaneous
space and reducing renal clearance
·
The PEGylation of insulin lispro with a 20-kDa
polyethylene glycol moiety at lysing B28 increases the hydrodynamic size to a
dhydrodynamic diameter that is 4 times that of insulin lispro.
·
Phase II studies have been completed in T1DM and
T2DM patients
·
Advantages
o
In T1DM, vs. glargine, 8 week, cross-over study,
morning injection
§
Non-inferior/superior for daily mean BG, A1c,
fasting BG variability
§
23% less prandial dose
§
loss in body weight (compared to glargine that
had a gain in body weight)
§
less nocturnal hypoglycemia, but MORE
hypoglycemia overall
o
In T2DM vs. glargine, 12 weeks, parallel group,
N=93, morning injection
§
Non-inferior fasting BG, A1c
§
Loss in body weight (gain with glargine)
§
Hypoglcyemia – less nocturnal and time spent
overall
·
Disadvantages
o
Need more data in pharmacodynamics profile in
T1DM
o
Not enough information of day-to-day
reproducibility
o
How to titrate?
o
In T1DM vs. glargine phase II study
§
Higher ALT, AST, Tg, LDL; lower HDL
§
More hypoglycemia overall?
o
In T2DM vs. garlgine
§
ALT, AST, (WNL) higher
§
Tg higher; ALT, AST, HDL, LDL no different
o
No yet approved in Canada
Bolus Insulin
Hyaluronidase
Coadministration
·
Hyaluronidase catalyzes the cleavage of
hyaluronan in the subcutaneous space, resulting in enhanced permeation of
coadministered agents and greater exposure in the capillary bed
·
Coadministration of engineered recombinatnt
human hyaluronidase (rHuPH20) increases the absorption and dispersion of bolus
insulin, resulting in accelerated absorption, less intrasubject variability,
and reduced delay in absorption seen for higher doses of insulin
·
Faster absorption, faster excretion
·
Advantages
o
Less rapid/bolus insulin required in T1DM and
T2DM
o
Statistically significant reduction (p<0.05),
reduction by 5% (clinically significant?) in hypoglycemia in T1DM; no change in
hypoglycemia in T2DM patients
·
Disadvantages
o
Another injection with rapid insulin?
o
Dosing? Titration?
o
Long-term effects?
o
Not yet approved in Canada
Inhaled Insulin
·
Been around since 2006
·
Technosphere particles
o
Microparticles and microspheres in which insulin
can attach (2.5 um in diameter) - Perfect for inhalation
o
60% of the drug is emitted from device; 30-40%
of the drug is inhaled in the lungs; lower bioavailability
o
shorter Tmax, clearance is accelerated
·
T2DM – prandial inhaled insulin plus basal
insulin gargine vs. premix analog BID, 52 weeks, LANCET
o
More weight gain in premix analog
o
Lower FPG with inhaled insulin
o
Post-prandial glucose exposure for 1-2 hours
following a meal; premix had lower blood sugars
o
Less hypoglycemia with inhaled insulin plus
garlgine vs. premixed analog BID
o
LIMITATION of study – not really comparing
·
T1DM, 52 weeks, technosphere insulin + prandial
vs. glargine + prandial
o
SMBG – no difference, FPG lower with TI than
with aspart
o
No difference in proportion of patients
achieving glycemic targets
·
Advantages
o
Patient satisfaction
o
Ease of administration
o
Comfort
o
Convenience
o
Mealtime flexibility
o
Ease of taking insulin many times a day
o
Improved QOL
o
Similar glycemic outcomes to SC rapid-acting
insulin
§
Lower overnight BG values
o
Similar rates of hypoglycemia and weight gain;
somewhat less with technosphere insulin
·
Disadvantages
o
Pulmonary Issues
§
Non-productive cough
§
Decreases FEV1 progresses over 6 months, but
stabilizes at 2 years
§
Decrease in diffusion capacity
o
Long-term effects?
o
Insufficient studies vs. analogs
o
Potential use and/or bridge to patients with
needle phobia, SC insulin resistance
Not yet approved in Canada
For more details, refer to Cheng AYY, New Developments in
Insulin Therapy – Expanding our Knowledge of Current and Emerging Treatment
Options. A report from the 72nd Annual Scientific Sessions of the
American Diabetes Association. June 8-12, 2012 – Philadelphia, Pennsylvania.
Scientific Update.
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