LUIGI MENEGHINI, MD, MBA

Division of Endocrinology, Department of Internal Medicine,

University of Texas Southwestern Medical Center and
Parkland Health & Hospital System, Dallas, TX

New insulin preparations:

A primer for the clinician

T
 ABSTRACT he first isolation and successful extraction of
The importance of glycemic control in preventing the insulin in 1921 opened an important chapter
chronic and devastating complications of diabetes is in the management of diabetes, especially for
well established. Insulin administration is an important patients with profound insulin deficiency. At
therapeutic option for managing diabetes, particularly for that time, a 14-year-old patient who was dying from
patients with profound insulin deficiency. Many insulin type 1 diabetes received the first insulin injection—a
formulations are on the market, including short-acting canine pancreatic extract. It was a lifesaving treat-
insulin analogues, inhaled insulin, concentrated insulin, ment. Within a few months of insulin administration,
and basal insulin. Each category has a unique onset, peak, the patient regained weight and health and went on
and duration of action. This article reviews the differing to live another 13 years before succumbing to pneu-
pharmacokinetic and pharmacodynamic properties and monia and chronic complications of hyperglycemia.
safety and efficacy data, and discusses the implications While the introduction of regular insulin from ani-
for clinical practice. mal extracts provided lifesaving therapy for patients
with type 1 diabetes, it was the introduction of prot-
 KEY POINTS aminated insulin in 1946 that provided more extended
“basal” coverage to taper some of the large glycemic
Insulin extracted from an animal pancreas was first
fluctuations that occurred with the administration of
administered in 1921; the first insulin analogue was
regular insulin two to three times daily. The use of a
marketed in 1996.
split-mix approach with twice-daily administration of
a combination of regular insulin plus either insulin
Insulin is considered the therapeutic standard in patients neutral protamine Hagedorn (NPH) or insulin lente
with advanced insulin deficiency. provided overall better control with fewer episodes of
hypoglycemia or severe hyperglycemia.
Types of available insulin products have differing onset, Insulin was the first protein to be sequenced (in
peak, and duration of action ranging from ultra-short- 1955), and it became the first human protein to be
acting to ultra-long-acting. manufactured through human recombinant technol-
ogy. It was introduced into clinical practice in 1982
The US Food and Drug Administration approved an as synthetic “human” insulin, with the advantage of
inhaled insulin product in 2014; all other products are being less allergenic than animal insulin preparations.
administered subcutaneously. Human insulin eventually replaced all of the animal
insulin preparations in the US market.
Concentrated insulin preparations provide an alternative The pursuit of tight glycemic control as an effec-
for patients requiring consistently high daily doses of tive strategy to prevent the chronic and devastating
insulin. complications of the disease was confirmed in 1993
by publication of the Diabetes Control and Compli-
cations Trial (DCCT), which undeniably established
the relationship between normalization of glycemia
and prevention of microvascular complications in
Dr. Meneghini has reported receipt of consulting/advisory fees from Novo patients with type 1 diabetes.1 The UK Prospective
Nordisk and Sanofi-Aventis. Diabetes Study, demonstrating a similar relationship
doi:10.3949/ccjm.83.s1.05 in type 2 diabetes, was soon to follow.2 In both trials,

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INSULIN PREPARATIONS

TABLE 1 TABLE 2
Insulin products marketed in the United States Metabolic control results from meta-analysis of
studies comparing short-acting insulin analogues
InsuIin (Brand) with human regular insulin in patients with type 1
Rapid-acting or type 2 diabetes mellitus (DM)
Insulin aspart (NovoLog)
Insulin lispro (Humalog) Patients
Insulin glulisine (Apidra) Type 1 DM Type 2 DM

Short-acting HbA1c
Regular insulin (Humulin R, Novolin R/ReliOn R) No. studies 22 5
WMD (95% CI) −0.1%a 0.0%
Intermediate, basal (−0.2 to −0.1) (−0.1 to 0.0)
NPH insulin (Humulin N, Novolin N/ReliOn N) Continuous SC injection −0.2%a —
subgroup (7 studies) (−0.3 to −0.1) —
Basal analogues Multiple dose injections −0.1% —
Insulin glargine U-100 (Lantus, Basaglar) subgroup (15 studies) (−0.1 to 0.0) —
Insulin detemir (Levemir)
Overall hypoglycemia
Longer-acting basal analogues No. studies 10 10
Insulin glargine U-300 (Toujeo) WMD mean events/pt/mo −0.2% −0.2%
Insulin degludec (Tresiba) (95% CI) (−1.1 to 0.7) (−0.5 to 0.1)

Premixed Severe hypoglycemia

75% Insulin lispro protamine/25% insulin lispro No. studies, 28 Not reported Not reported
(Humalog mix 75/25) Median events/100 person- 21.8 vs 46.1 0.3 vs 1.4
50% Insulin lispro protamine/50% insulin lispro years, insulin analogue vs
(Humalog mix 50/50) regular insulin
70% Insulin lispro protamine/30% insulin aspart
(Novolog mix 70/30) a
Statistically significant in favor of insulin analogues vs regular insulin.
70% NPH insulin/30% regular insulin (Humulin, Novolin/ CI = confidence interval; SC = subcutaneous; WMD = weighted mean difference.
ReliOn) Based on data in Siebenhofer A, Plank J, Berghold A, et al. Short acting insulin
70% Insulin degludec/30% insulin aspart (Ryzodeg 70/30) analogues versus regular human insulin in patients with diabetes mellitus.
Cochrane Database Syst Rev 2006; 19:CD003287.
Inhaled
Technosphere insulin oral-inhalation system (Afrezza)

NPH = neutral protamine Hagedorn. lente insulin, and the delivery of the basal compo-
nent through continuous subcutaneous (SC) insulin
infusion using an insulin pump further facilitated
achievement of near-normal glycemia.
the follow-up observation periods further under-
Insulin products continue to be refined and new
scored the importance of early glycemic control by
formulations and molecular entities developed (Table
showing both sustained reductions in microvascular
1). The following sections review the current insu-
complications (retinopathy, nephropathy, and neu-
lin products, their pharmacologic profiles, and their
ropathy) and statistically significant decreases in the
clinical roles in diabetes practice.
risk of a cardiovascular event.3,4 Of note, it was the
introduction in clinical practice of safer and more
user-friendly insulin options that made these gains in  INSULIN ANALOGUES
glycemic control possible. In 1996, the first short-acting insulin analogue (or
With the publication of the DCCT results,1 insulin-receptor ligand), lispro, was brought to mar-
physiologic insulin replacement became the thera- ket. In lispro, the penultimate lysine and proline
peutic standard in patients with advanced insulin amino acids on the end of the C-terminal of the
deficiency, demonstrating that lowering hemoglobin beta-chain of human insulin are reversed, facilitating
A1c (HbA1c) and mitigating glycemic variability faster absorption of the insulin through the greater
translated into microvascular risk reduction. The use availability of insulin monomers following SC depot
of longer-acting insulin preparations, such as ultra- injection.
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 MENEGHINI

Baseline-corrected Baseline-corrected
serum insulin concentrations glucose infusion rate
80 8

8 Units inhaled insulin 8 Units inhaled insulin

70 7
8 Units insulin lispro 8 Units insulin lispro
N = 12

Glucose infusion rate (mg/kg/min)

60 6 N = 12

50 5
Insulin (µU/mL)

40 4

30 3

20 2

10 1

0 0
−30 0 30 60 90 120 150 180 210 240 270 300 330 360 −30 0 30 60 90 120 150 180 210 240 270 300 330 360
Time (minutes) Time (minutes)

FIGURE 1. Serum insulin concentrations and glucose infusion rate of inhaled insulin for inhaled vs insulin lispro in patients with type 1 diabetes.
Data from Afrezza (insulin human) inhalation powder [package insert]. Danbury, CT: MannKind Corp; 2014.

The three short-acting insulin analogues—lispro, ferent when administered to obese, insulin-resistant
aspart, and glulisine—have similar pharmacokinetic patients with type 2 diabetes, in whom the onset of
and pharmacodynamic properties, with earlier onset action is delayed and the biologic activity consider-
and peak of biologic action, and shorter duration of ably reduced.8
activity than regular insulin. Potentially, these char-
acteristics should translate into greater administra-  INHALED INSULIN
tion flexibility (patients can inject anywhere from 20 A recent entry into the short-acting insulin market-
minutes before to 20 minutes after the start of the place—Technosphere oral-inhaled insulin (Afrezza)—
meal), better control of postprandial hyperglycemia, was US Food and Drug Administration (FDA)-
and less risk of late prandial hypoglycemia (3 to 6 approved in 2014. Inhaled insulin has low bioavail-
hours after the meal). In a meta-analysis comparing ability but is absorbed much more rapidly into the
short-acting analogues with human regular insulin, circulation than the current short-acting insulin ana-
the most relevant difference reported was a lower risk logues and has a shorter duration of biologic activity.
of severe hypoglycemia with the analogue prepara- However, the pharmacodynamics of inhaled insu-
tions5 (Table 2). There might be an advantage with lin, when compared with insulin lispro, show only
regards to bedtime and overnight hypoglycemia when a slightly faster onset of action and a lower peak of
using short-acting analogues, especially if a protami- biologic activity9 (Figure 1). Studies comparing the
nated insulin is used for overnight basal coverage.6 efficacy and safety of inhaled insulin with short-act-
While short-acting analogues have been approved ing analogues or premix insulin have demonstrated
for administration following a meal, postprandial con- equivalent or less effective blood glucose-lowering
trol is clearly better if these preparations are injected effect and equivalent or lower risk of hypoglycemia.10
prior to the meal, ideally 15 to 20 minutes before, For example, in trials of aspart insulin in patients with
to allow time to enter the circulation.7 Addition- type 1 diabetes, inhaled insulin had statistically less
ally, the pharmacokinetics and biologic activity of reduction in HbA1c; in only one of the two trials did
short-acting insulin analogues appear to be very dif- it show less hypoglycemia risk. Another trial compar-
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INSULIN PREPARATIONS

ing inhaled insulin plus basal insulin to premix aspart insulin syringes, a 1-unit measure of U-500 corre-
70/30 showed equivalent HbA1c reductions, but less sponds to a 5-unit delivery of regular insulin.
hypoglycemia with inhaled insulin.10 To minimize confusion, regular U-500 prescrip-
Inhaled insulin should not be used by smokers, tions should be made out in volume rather than
patients with chronic lung disease (such as asthma units, but this difference must be clearly explained to
and chronic obstructive pulmonary disease), and those patients to avoid overdosing. For example, 0.01 mL of
with acute episodes of bronchospasm. In patients who U-500 equates to 5 units of insulin, but it corresponds
have a history of or are at risk for lung cancer, the to the 1-unit mark of the standard U-100 insulin
benefits of using inhaled insulin need to be carefully syringe. Newer concentrated insulin preparations on
weighed against the potential risks, especially given the market have avoided this confusion by providing
the increase in lung cancer events in smokers that was measured doses in an insulin pen delivery system. For
observed with the prior inhaled-insulin preparation example, insulin lispro U-200 (Humalog U-200), a
Exubera.11 Baseline and follow-up spirometry needs twofold concentration of insulin lispro U-100 with
to be implemented for those using inhaled insulin to similar pharmacodynamics, is only available in a pre-
exclude clinically significant changes in forced expira- filled pen. Using insulin pen technology, a 1-unit dose
tory volume in 1 second. Dosing of inhaled techno- of insulin actually corresponds to 1 unit of insulin,
sphere insulin is done via single-use cartridges of 4-, thereby removing any possible confusion regarding
8-, or 12-unit composition, making titration of smaller the prescription or administration of the correct insu-
insulin increments more of a challenge. Patient lin dose. Insulin lispro U-200 offers the convenience
reported outcomes in trials of inhaled insulin report of holding more insulin per pen; it contains 600 units
variable effect (equivalent or favorable) on diabetes of insulin per pen compared with 300 units in the
worries, health-related quality of life, or perceptions of lispro U-100 pen.
insulin therapy, satisfaction, or preference.12,13
 BASAL INSULIN
 CONCENTRATED INSULIN Currently available basal insulin preparations include
Concentrated insulin preparations have been avail- insulin NPH (Humulin N, Novolin N), insulin
able in clinical practice for many years and have been glargine U-100 (Lantus), insulin detemir (Levemir),
implemented with variable success. For example, and the 2015 FDA-approved formulations insu-
Humulin R U-500 is a concentrated human regular lin glargine U-300 (Toujeo) and insulin degludec
insulin product (five times more concentrated than (Tresiba). The basal analogues introduced in the year
U-100) that has been used in patients requiring con- 2000 with glargine U-100 were meant to fill the void
sistently high daily doses of insulin (usually > 200 U/ left when the long-acting insulin ultralente animal
day). Nonrandomized studies have shown significant preparations were pulled from the market in the early
improvement in glycemic control comparing pre- and 1990s. The basal analogues have a longer duration
post-intervention periods in patients switched from of action than insulin NPH and, more importantly,
U-100 prandial insulin preparations to U-500 regular have more stable and consistent biologic activity over
insulin.14 Given the slight differences in pharmaco- a 24-hour period, resulting in more predictable glyce-
dynamic profiles between regular U-100 and U-500 mic levels and a lower risk of hypoglycemia.16–18
insulin preparations,15 a randomized controlled trial Three insulin analogue preparations—glargine
comparing a U-500 insulin strategy with other cur- U-300 and degludec (both FDA-approved) and
rently available alternatives in very insulin-resistant pegylated lispro (currently in phase 3 trials)—have
patients will be needed to draw objective conclusions demonstrated longer protraction of biologic activity
regarding the efficacy and safety of this concentrated than glargine U-100, considered the current tech-
insulin preparation. nical standard for basal insulin replacement. These
For patients and providers who opt for a trial of three “second-generation” basal insulin analogues
regular U-500 insulin, a number of issues need to be have pharmacodynamic activity that extends beyond
considered to mitigate risks and optimize benefits of 24 hours. When compared with glargine U-100
using this concentrated insulin. First and foremost insulin, they exhibited fewer pronounced peaks of
is the frequent confusion in the communication biologic activity and less pharmacokinetic variabil-
between provider, pharmacy, and patient regarding ity, with similar glycemic control (as determined by
the correct insulin dose to be administered. Because HbA1c) but with an even lower risk of hypoglycemia,
regular U-500 insulin is administered with U-100 especially nocturnal hypoglycemia.19–21
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Injected insulin Insulin in SC depot Insulin in circulation

Units
Units remaining Maximum
added from prior units Units
each injections present in absorbed into
day (t1/2 24 h) 24 h interval circulation

FIGURE 2. Example of time to reach steady state without inappropriate accumulation of basal insulin using a simplified one-compartment
model (10 U, with half-life ~24 hours). Because dosing frequency is approximately equal to half-life, insulin only accumulates until steady state is
reached, at which time the daily injected dose is balanced by elimination. SC = subcutaneous; t1/2 = half-life.
Reprinted from Endocrine Practice (Heise T, Meneghini LF. Insulin stacking versus therapeutic accumulation: Understanding the differences.
Endocr Pract 2014; 20:75–83), © 2014 with permission from the American Association of Clinical Endocrinologists.

The extended biologic activity raises concern for presumed to account for much of the protracted
potential insulin stacking and subsequent hypoglyce- absorption of glargine U-300 from the SC tissues.
mia, which should be easily mitigated by restricting The metabolism and elimination of glargine U-300
basal insulin dose adjustments to no more frequently is similar to that of the original compound, with
than every 3 to 4 days, which corresponds to the time formation of two active metabolites: M1 (the prin-
needed for these preparations to reach 90% or more cipal active moiety) and M2. Biologic steady state is
of their effective steady state22 (Figure 2). Indeed, achieved after 4 to 5 days of once-daily injections.24
most of the clinical trials comparing these basal insu- When compared with glargine U-100 in patients
lin preparations with glargine U-100 show a lower with type 1 diabetes, insulin glargine U-300 at doses
risk of hypoglycemia when basal dose adjustments are of 0.4 U/kg produced more stable insulin concentra-
carried out weekly and no more frequently than every tions and glucose-lowering effect with a longer dura-
3 days.23 tion of action at steady state, as reflected by tight
Insulin glargine U-300 is essentially a threefold glucose control being maintained for about 5 hours
concentrated preparation of insulin glargine U-100 longer (median of 30 hours).25 A meta-analysis of the
that results in a two-thirds volume reduction and EDITION I to III clinical trials in patients with type
a one-half reduction in depot surface following SC 2 diabetes at various stages of treatment found similar
administration. The reduced depot surface area is glucose-lowering effects for glargine U-300 compared
CL E VE L AND CL I NI C J OURNAL OF MED IC INE VOLUME 83 • SUPPLEMENT 1 MAY 2016 S31
INSULIN PREPARATIONS

with glargine U-100 but a lower rate of nonsevere ing of insulin dose administration). While the latter
hypoglycemia.20 Of note was the need for 10% to is presumed to improve patient adherence, this has
15% more units of insulin for glargine U-300 in these yet to be confirmed. Compared with synthetic human
clinical trials. Insulin glargine U-300 is available only insulin preparations (regular insulin, NPH, and pre-
in a 1.5 mL disposable prefilled pen, which contains mix 70/30 insulin), which can be obtained in certain
450 units of insulin. Because the dose counter on pharmacies at a discount (usually around 3 cents per
the pen window corresponds to the actual number of unit of insulin), the currently available insulin ana-
units of insulin to be injected, no dose recalculation logues are considerably more expensive (around 16 to
is required by the patient or provider. 27 cents per unit of insulin).
Insulin degludec is another ultra-long-acting basal Within the guidelines for initiation and intensi-
insulin analogue with a half-life at steady state of fication of the insulin regimen using basal insulin
greater than 25 hours.26 In comparison, the half-life of formulations, the clinician will need to balance the
insulin glargine U-100 in that same study was reported potential benefits and current costs for the treatment
as 12.1 hours. Further, insulin degludec exhibited of the individual patient. Clearly, as patients with
flatter and more stable biologic activity, more evenly diabetes are brought closer to their glycemic goals
distributed over the course of a 24-hour period than with insulin options, they stand to increasingly bene-
insulin glargine U-100. The protraction mechanism fit from formulations that provide more consistent
is based on the formation of long strings of multi- glycemic response and less risk of hypoglycemia. For
hexamers, facilitated by a 16-carbon fatty acid chain those who are unable to afford the higher costs, espe-
linked via a glutamic acid spacer to the terminal end cially if their glycemic control is far from the desired
of the B-chain of the insulin molecule.27 In studies of target, the use of synthetic human insulin formula-
patients with type 2 diabetes at various stages of treat- tions may be entirely appropriate. In this era of indi-
ment, insulin degludec also demonstrated lower risk vidualized care and prescriptions, clinicians have a
of nonsevere hypoglycemia for an equivalent level of range of insulin treatment options that will facilitate
HbA1c control achieved.19 patients reaching appropriate goals.
The flexibility of administration time for an ultra-
long-acting insulin preparation such as degludec was  REFERENCES
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glycaemia with new insulin glargine 300 U/ml versus glargine 100 Correspondence: Luigi Meneghini, MD, MBA, Professor of Internal Medicine,
U/ml in people with type 2 diabetes. Diabetes Obes Metab 2015; University of Texas Southwestern Medical Center, Division of Endocrinology,
17:859–867. 5323 Harry Hines Blvd., Dallas, TX 75390; Luigi.Meneghini@UTSouthwestern.edu

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