Insulin Glargine: A New Basal Insulin

Abstract

To review the pharmacology, pharmacokinetics, dosing guidelines, adverse effects, drug interactions, and clinical efficacy of insulin glargine.
Primary and review articles regarding insulin glargine were identified by MEDLINE search (1966-July 2001); abstracts were identified through Institute for Scientific Information Web of Science (1995-July 2001) and the American Diabetes Association. Additional information was obtained from the insulin glargine product information.
All of the articles and meeting abstracts identified from the data sources were evaluated, and all information deemed relevant was included in this review. Priority was placed on data from the primary medical literature.
Insulin glargine is a long-acting, recombinant human insulin analog that is given once daily as a basal source of insulin in patients with type 1 or type 2 diabetes mellitus. Modification of the basic insulin structure has produced a new insulin that is soluble at an acidic pH, but precipitates in the subcutaneous tissue and is slowly released from a depot. Insulin glargine has a slower onset of action than NPH insulin and a longer duration of action with no peak activity. Once-daily administration of insulin glargine has comparable efficacy to that of NPH insulin administered once or twice daily in basal-bolus regimens when used in combination with intermittent doses of regular insulin or insulin lispro in patients with type 1 and type 2 diabetes, and in conjunction with oral antidiabetic agents in patients with type 2 diabetes. Overall, insulin glargine has an incidence of hypoglycemia comparable to or less than that of NPH insulin, with a reduced incidence of nocturnal hypoglycemia compared with NPH insulin seen in some studies.
Insulin glargine is a long-acting insulin analog capable of providing 24-hour basal insulin coverage when administered once daily at bedtime. Its activity profile, which lacks a pronounced peak, more closely resembles that of endogenous basal insulin than that of other intermediate- or long-acting insulins and appears more likely to be associated with a reduced incidence of hypoglycemia, particularly nocturnal hypoglycemia. Insulin glargine physiologically provides basal insulin but, for most patients, the addition of a rapid-acting insulin, like insulin lispro, before or with meals will need to be included in the treatment regimen to achieve optimal management of blood glucose concentrations.

Full text

I
nsulin glargine (HOE 901; 21
A
-Gly-30
B
a-L-Arg-30
B
b-L-
Arg-human insulin) is a long-acting, recombinant human
insulin analog that is given once daily as a basal source of
insulin in patients. It is indicated for once-daily subcuta-
neous administration at bedtime in the treatment of adults
and children with type 1 diabetes mellitus and adults with
type 2 diabetes mellitus who require basal insulin for the
control of hyperglycemia.
1
Patients with type 1 diabetes
and many patients with type 2 diabetes receiving basal in-
sulin therapy require the addition of a rapid-acting insulin
to their regimen to mimic the endogenous basal/bolus in-
sulin response and achieve optimal management of blood
glucose concentrations.
Insulin glargine received Food and Drug Administration
approval in 2000 and was marketed in May 2001. It is
available as a clear, colorless solution in 10-mL vials and
The Annals of Pharmacotherapy
■
2002 June, Volume 36
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1019
Insulin Glargine: A New Basal Insulin
Terri L Levien, Danial E Baker, John R White Jr, and R Keith Campbell
ARTICLES
www.theannals.com
Formulary Forum
Author information provided at the end of the text.
Lantus (insulin glargine, Aventis Pharmaceuticals).
OBJECTIVE: To review the pharmacology, pharmacokinetics, dosing guidelines, adverse effects, drug interactions, and clinical
efficacy of insulin glargine.
DATA SOURCES: Primary and review articles regarding insulin glargine were identified by MEDLINE search (1966–July 2001);
abstracts were identified through Institute for Scientific Information Web of Science (1995–July 2001) and the American Diabetes
Association. Additional information was obtained from the insulin glargine product information.
STUDY SELECTION AND DATA EXTRACTION: All of the articles and meeting abstracts identified from the data sources were evaluated,
and all information deemed relevant was included in this review. Priority was placed on data from the primary medical literature.
DATA SYNTHESIS: Insulin glargine is a long-acting, recombinant human insulin analog that is given once daily as a basal source of
insulin in patients with type 1 or type 2 diabetes mellitus. Modification of the basic insulin structure has produced a new insulin that is
soluble at an acidic pH, but precipitates in the subcutaneous tissue and is slowly released from a depot. Insulin glargine has a
slower onset of action than NPH insulin and a longer duration of action with no peak activity. Once-daily administration of insulin
glargine has comparable efficacy to that of NPH insulin administered once or twice daily in basal-bolus regimens when used in
combination with intermittent doses of regular insulin or insulin lispro in patients with type 1 and type 2 diabetes, and in conjunction
with oral antidiabetic agents in patients with type 2 diabetes. Overall, insulin glargine has an incidence of hypoglycemia comparable
to or less than that of NPH insulin, with a reduced incidence of nocturnal hypoglycemia compared with NPH insulin seen in some
studies.
CONCLUSIONS: Insulin glargine is a long-acting insulin analog capable of providing 24-hour basal insulin coverage when
administered once daily at bedtime. Its activity profile, which lacks a pronounced peak, more closely resembles that of endogenous
basal insulin than that of other intermediate- or long-acting insulins and appears more likely to be associated with a reduced
incidence of hypoglycemia, particularly nocturnal hypoglycemia. Insulin glargine physiologically provides basal insulin but, for most
patients, the addition of a rapid-acting insulin, like insulin lispro, before or with meals will need to be included in the treatment
regimen to achieve optimal management of blood glucose concentrations.
KEY WORDS: diabetes mellitus, insulin glargine, Lantus.
Ann Pharmacother 2002;36:1019-27.
THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT. ACPE UNIVERSAL PROGRAM NUMBER: 407-000-02-017-H01
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will also be available in 3-mL cartridges for use with the
OptiPen One insulin delivery device.
1
Each milliliter of in-
sulin glargine injection contains insulin glargine 100 units,
zinc 30 µg, m-cresol 2.7 mg, glycerol 85% 20 mg, and wa-
ter for injection.
Methods for Selection and Assessment of
Literature
Primary and review articles regarding insulin glargine
were identified by MEDLINE search (1966–July 2001);
abstracts were identified through the Institute for Scientific
Information Web of Science (1995–July 2001) and the
American Diabetes Association. Additional information
was obtained from the insulin glargine product informa-
tion. All of the articles and meeting abstracts identified from
the data sources were evaluated, and all information deemed
relevant was included in this review. Priority was given to
clinical studies that evaluated the pharmacology, pharma-
cokinetics, safety, and effectiveness of insulin glargine. Case
studies were not included unless they involved reports of
unique and important adverse events.
Pharmacology
Intermediate- and long-acting insulin products are used
in type 1 and type 2 diabetes to mimic basal insulin secre-
tion. Unfortunately, intermediate-acting insulin products,
such as NPH and Lente insulin, do not provide 24-hour
basal insulin effects in many patients and produce high
peak insulin concentrations that can increase the risk of
nocturnal hypoglycemia.
2
Ultralente insulin has a longer du-
ration of action than NPH; however, a high degree of intra-
subject and intersubject variability in absorption (25–50%)
and onset of effect has been observed with these interme-
diate- and long-acting insulins.
2,3
Insulin glargine is a human insulin analog produced by
recombinant DNA technology that is structurally modified
to create a long-acting insulin with reduced variability in
absorption. Insulin glargine was created by the addition of
2 arginines at the C-terminus of the B chain and the substi-
tution of glycine for asparagine in position A21 (Figure
1).
1,2,4
The isoelectric point of human insulin is at pH 5.4. The
addition of the positively charged amino acids to the in-
sulin glargine molecule shifted the isoelectric point to pH
6.8.
4
Insulin glargine injection solution is formulated to a
pH of 4, where it is completely soluble.
1,4
Insulin glargine
is less soluble at the neutral pH found at the injection site,
so insulin glargine forms a microprecipitate following sub-
cutaneous injection.
1,2,5
When insulin glargine is injected
into the subcutaneous tissue (pH 7.4), the acidic solution is
neutralized and microprecipitates form in the subcutaneous
tissue. These crystals slowly dissolve, resulting in a slow
release of insulin dimers and monomers to the tissue and
bloodstream with no pronounced peak concentration.
1,4
The
glycine substitution in the insulin also contributes to a dense
crystal structure with a low water content.
4
The addition of
zinc to the insulin glargine formulation delays the release
of the insulin dimers and monomers even further, prolong-
ing its duration of action.
2,6
The bioactivity of insulin glargine is 100% of that of hu-
man insulin.
2,5
When administered intravenously, insulin
glargine produces a blood glucose response identical to
that of intravenously administered regular human insulin.
2
Insulin glargine behaves like regular human insulin with
respect to insulin receptor binding and activity and insulin-
like growth factor 1 (IGF-1) receptor–mediated signaling.
It has, however, demonstrated 3- to 14-fold increased IGF-
1 receptor affinity and mitogenic potency compared with
human insulin, the clinical significance of which is cur-
rently unknown.
7-12
Pharmacokinetics/Pharmacodynamics
Following subcutaneous administration, the onset of ac-
tion of insulin glargine occurs within 1 hour.
13
Full activity
is reached within 4–5 hours and persists at a constant ef-
fect for 24 hours.
2,14
No significant insulin peak activity oc-
curs after subcutaneous administration, and a flat serum in-
sulin profile is observed between 1 and 24 hours.
4,13-19
In
contrast, NPH insulin has a quicker onset, more pro-
nounced peak, and a shorter duration of action.
The pharmacokinetics and pharmacodynamics of in-
sulin glargine, NPH insulin, and ultralente insulin have been
compared in several euglycemic glucose clamp studies.
Overall, insulin glargine had a relatively constant effect, with
no notable peak activity and a duration exceeding that of
NPH. The results of 1 crossover glucose clamp study com-
paring insulin glargine and NPH insulin in 20 patients with
type 1 diabetes are shown in Figure 2.
1
In that study,
1,13
the
median time from injection to end of effect was 14.5 hours
with NPH insulin and 24 hours (the end of the observation
period) with insulin glargine. In another crossover glucose
clamp trial
17
enrolling 20 patients with type 1 diabetes, the
pharmacokinetics of insulin glargine were found to more
closely resemble those of continuous subcutaneous insulin
lispro than either NPH insulin or ultralente insulin. Al-
though the onset of action of insulin glargine (1.5 h) was
slower than with the subcutaneous infusions of insulin
lispro (0.5 h), NPH insulin (0.8 h), or ultralente insulin (1
h), no peak concentration or peak activity was observed
with insulin glargine and less interindividual variability
1020
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2002 June, Volume 36
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TL Levien et al.
Figure 1. Insulin glargine graphic formula.
1

was observed. Plasma insulin concentrations reached a
plateau between 3 and 24 hours after insulin glargine admin-
istration. Similarly, plasma insulin concentrations reached a
plateau between 4 and 24 hours with the continuous sub-
cutaneous infusion of insulin lispro. The duration of action
of insulin glargine (20.5 h) was similar to that of ultralente
(19 h), greater than that of NPH (13.2 h), and less than that
of the 24-hour continuous subcutaneous insulin lispro
(23.5 h).
17
NPH insulin, ultralente insulin, and insulin glargine have
also been compared in 12 healthy subjects in a glucose
clamp study.
14
Peak concentrations of exogenous serum in-
sulin (calculated from insulin concentration corrected by
C-peptide estimate of endogenous production) were 25
µunits/mL 4 hours following NPH insulin administration,
and they declined thereafter. Exogenous insulin concentra-
tions rose progressively to 9 µunits/mL 14–22 hours fol-
lowing ultralente administration. Exogenous insulin con-
centrations increased to 10 µunits/mL at 5 hours, with a
plateau observed at points beyond 4 hours following in-
sulin glargine administration. In comparison with NPH in-
sulin in another study,
15
insulin glargine was associated
with lower glucose consumption and therefore a lower
metabolic effect both during the first 4 hours after adminis-
tration and for 30 hours after administration. Unlike after
administration of NPH insulin and consistent with other
trials, no significant peak activity was observed with in-
sulin glargine.
Subcutaneous administration into the leg, arm, and ab-
domen produces similar absorption patterns.
19
Following
administration of radiolabeled insulin glargine, the time to
disappearance of 25% of the radioactivity, indicating ab-
sorption from the subcutaneous tissue, has been observed
within 8.8–15.3 hours.
19,20
In a study
20
comparing absorp-
tion of insulin glargine and NPH insulin following subcu-
taneous injection into the abdomen, the time to disappear-
ance of 25% of the radioactivity was 15 hours for insulin
glargine compared with 6.5 hours for NPH insulin. In an-
other study,
19
the time to disappearance of 25% of the ra-
dioactivity was 3.2 hours for NPH insulin compared with
8.8–11 hours with insulin glargine. These trials demon-
strate that the absorption of insulin glargine from subcuta-
neous tissue is more prolonged than that of NPH insulin.
In the subcutaneous depot, insulin glargine is partially
metabolized at the carboxyl terminus of the B chain to 2
active metabolites. These metabolites, 21
A
-Gly-insulin and
21
A
-Gly-des-30
B
-Thr-insulin, have in vitro activity similar
to that of endogenous insulin.
1
The effects of renal or hepatic impairment on the phar-
macokinetics of insulin glargine have not been studied. Re-
nal and hepatic dysfunction can result in increased circulat-
ing concentrations of insulin.
1
Clinical Studies
Insulin glargine administered subcutaneously once daily
at bedtime has been evaluated in numerous studies enrolling
patients with type 1 and type 2 diabetes, primarily in com-
parison with NPH insulin. Insulin glargine has been shown
to offer efficacy at least comparable to that of NPH insulin
administered once or twice daily with regard to effects on
fasting plasma glucose and glycosylated hemoglobin
(HbA
1C
). In several trials, insulin glargine has been associ-
ated with a reduced incidence of hypoglycemia, particular-
ly nocturnal hypoglycemia, compared with NPH insulin.
TYPE 1 DIABETES
Insulin glargine has been evaluated in 5 large, open-la-
bel, multicenter trials enrolling patients with type 1 dia-
betes previously treated with a regimen including NPH in-
sulin. In each study, patients either continued therapy with
NPH insulin administered once or twice daily or were
switched to therapy with insulin glargine administered
once daily at bedtime, while continuing their regimen of
bolus regular insulin or insulin lispro. Open-label design
was used in the trials due to the difference in product ap-
pearance. Blinded trials were not done because they would
have required a double-dummy design, and each patient
would receive twice as many injections. Results of these
studies are summarized in Table 1.
1,21-27
In each study, the
investigators combined the results for the NPH groups.
Insulin glargine was compared with NPH insulin in a
study
1,21
enrolling 534 patients with type 1 diabetes con-
trolled with a regimen of NPH plus regular insulin. In addi-
tion to premeal injections of regular human insulin, patients
received insulin glargine once daily at bedtime, NPH insulin
once daily at bedtime, or NPH twice daily for 28 weeks.
Median fasting plasma glucose was reduced to a greater ex-
tent with insulin glargine, although only small reductions in
HbA
1C
were observed in both groups. The mean basal in-
sulin dose decreased 4.1 units in the insulin glargine group,
but increased 1.8 units in the NPH group. The mean basal
insulin dose at the study’s end was 24.8 units in the insulin
glargine group and 31.3 units in the NPH insulin group. The
total daily insulin dose did not change in the insulin glargine
group (0.3 units), but increased slightly in the NPH group
Insulin Glargine: A New Basal Insulin
The Annals of Pharmacotherapy
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2002 June, Volume 36
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1021
www.theannals.com
Figure 2. Insulin glargine activity profile.
1
* = amount of glucose infused to
maintain constant plasma glucose concentrations.

(3.7 units). Symptomatic hypoglycemia occurred less fre-
quently in the insulin glargine–treated patients after the ini-
tial dose titration phase (39.9% vs. 49.2%; p = 0.0219). The
incidence of nocturnal hypoglycemia was also lower in the
insulin glargine group (18.2% vs. 27.1%; p = 0.0116), as
was the incidence of severe hypoglycemia confirmed by a
blood glucose concentration <36 mg/dL (1.9% vs. 5.6%; p
= 0.0117). In this trial, insulin glargine–treated patients were
reported to have experienced greater treatment satisfaction,
improved perception of frequency of hypoglycemia and hy-
perglycemia, and a trend toward greater psychological well-
being compared with the patients treated with NPH in-
sulin.
28,29
In a similar study
1
enrolling 585 patients with well-con-
trolled type 1 diabetes, small reductions in HbA
1C
and fast-
ing blood glucose concentration were observed during the
course of the study. The mean basal insulin dose decreased
1.7 units in the insulin glargine group and 0.3 units in the
NPH group. The total daily insulin dose decreased slightly
in the insulin glargine group (–1.1 units), but remained un-
changed in the NPH group (–0.1 units). The overall rate of
hypoglycemia was similar in the 2 treatment groups.
In a 28-week study,
22
insulin glargine administered once
daily was compared with NPH insulin administered twice
daily in 394 patients with type 1 diabetes previously treat-
ed with multiple daily injections of basal and regular in-
sulin. At study completion, a greater reduction in fasting
blood glucose was achieved in the insulin glargine–treated
patients, and more patients in that group achieved a target
fasting blood glucose concentration of 120 mg/dL (32.6%
vs. 21.3%; p = 0.015). Following a 1-month dosage titra-
tion period, symptomatic hypoglycemia (blood glucose
<50 mg/dL) occurred in 73.3% of insulin glargine–treated
patients compared with 81.7% of those who received NPH
insulin (p = 0.021). Symptomatic hypoglycemia (blood
glucose <36 mg/dL) occurred in 36.6% of insulin glargine–
treated patients compared with 46.2% of NPH insulin–treat-
ed patients (p = 0.033).
Insulin glargine or NPH insulin was administered in a
regimen with premeal insulin lispro in a trial
1,23
enrolling
619 patients with well-controlled type 1 diabetes. Insulin
doses were adjusted to achieve target fasting blood glucose
concentrations of 79–120 mg/dL. Only small reductions in
HbA
1C
were observed during the course of the study. Fast-
ing blood glucose concentrations were reduced to a greater
extent in the insulin glargine group. A target fasting blood
glucose of ≤119 mg/dL was reached in 29.6% of insulin
glargine–treated patients compared with 16.8% of patients
treated with NPH insulin. The mean basal insulin dose de-
creased 4.5 units in the insulin glargine group and in-
creased 0.9 units in the NPH group. The rate of hypo-
glycemia was comparable in the 2 groups. Injection site
1022
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TL Levien et al.
Table 1. Summary of Clinical Trials Evaluating Insulin Glargine
HbA
1C
FPG Change
a
Reference Study Design Regimen Change
a
(%) (mg/dL)
Type 1 diabetes mellitus
package insert (2001)
1
, open, 28 wk, premeal regular
Ratner et al. (2000)
21
n = 534 insulin glargine once daily at bedtime (n = 264) –0.16 –20.2
b
NPH insulin once daily at bedtime or NPH insulin twice daily (n = 270) –0.21 –16.9
package insert (2001)
1
open, 28 wk, premeal regular
n = 585 insulin glargine once daily at bedtime (n = 292) 0.21 –21.1
NPH insulin once daily at bedtime or NPH insulin twice daily (n = 293) 0.1 –16
Hershon et al. (2001)
22
open, 28 wk, premeal regular
n = 394 insulin glargine once daily at bedtime –25
b
NPH insulin twice daily –14
package insert (2001)
1
, open, 16 wk, premeal insulin lispro
Raskin et al. (2000)
23
n = 619 insulin glargine once daily at bedtime (n = 310) –0.06 –30.6
c
NPH insulin once daily at bedtime or NPH insulin twice daily (n = 309) –0.11 –10.8
package insert (2001)
1
, open, 28 wk, premeal regular
Schoenle et al. (1999)
24
n = 349 insulin glargine once daily at bedtime (n = 174) 0.28 –23.2
d
(6–15 y) NPH insulin once daily at bedtime or NPH insulin twice daily (n = 175) 0.27 –12.2
Type 2 diabetes mellitus
package insert (2001)
1
, open, 52-wk, continued oral agents
Yki-Jarvinen et al. (2000)
25
n = 570 insulin glargine once daily at bedtime (n = 289) –0.46 –49
NPH insulin once daily at bedtime (n = 281) –0.38 –46.3
package insert (2001)
1
, open, 28 wk, premeal regular insulin
Rosenstock et al. (2001)
26
n = 518 insulin glargine once daily at bedtime (n = 259) –0.41 –23.8
NPH insulin once daily at bedtime or NPH insulin twice daily (n = 259) –0.38 –21.6
Fonseca et al. (2001)
27
open, 28 wk, premeal regular insulin (if part of previous therapy)
n = 100 insulin glargine once daily at bedtime –0.35 –17.1
NPH insulin once daily at bedtime or NPH insulin twice daily –0.44 –20.3
FPG = fasting plasma glucose; HbA
1C
= glycosylated hemoglobin.
a
Mean change from baseline.
b
p < 0.0145 vs. NPH insulin.
c
p < 0.014 vs. NPH insulin.
d
p < 0.0001 vs. NPH insulin.
e
p = 0.0315 vs. NPH insulin.

pain was reported more frequently in the insulin glargine
group. Weight gain was significantly less in patients who
received insulin glargine (0.12 vs. 0.54 kg, respectively; p
= 0.034).
Insulin glargine and NPH insulin have also been com-
pared in 349 children 6–15 years of age.
1,24
As in the other
studies, only small changes in HbA
1C
were observed dur-
ing the course of this study. Fasting blood glucose concen-
trations declined in both groups. The mean basal insulin
dose decreased 1.3 units in the insulin glargine group and
increased by 2.4 units in the NPH group. The total daily in-
sulin dose increased slightly in the insulin glargine group
(1.9 units) and in the NPH group (3.4 units). The overall
incidence of hypoglycemia was similar in the 2 treatment
groups, although children in the insulin glargine group expe-
rienced slightly less frequent severe hypoglycemia (22.4%
vs. 28.6%), nocturnal hypoglycemia (48.3% vs. 50.9%),
and severe nocturnal hypoglycemia (12.6% vs. 17.7%).
Two insulin glargine formulations were evaluated in
comparison with NPH insulin in a 4-week study
30,31
en-
rolling 256 patients with type 1 diabetes previously treated
with a basal-bolus regimen. In addition to premeal injec-
tions of regular human insulin, patients received insulin
glargine (containing 30 or 80 µg/mL of zinc) once daily at
bedtime or NPH insulin once daily at bedtime or twice dai-
ly according to their prestudy regimen. At study entry, the
mean fasting plasma glucose concentration was 218 mg/dL,
and the mean HbA
1C
was 7.9%. After 4 weeks of therapy,
the fasting plasma glucose was 166 mg/dL with insulin
glargine treatment compared with 204 mg/dL in subjects
on NPH insulin (p = 0.0001). Hypoglycemia was common
in all treatment groups, occurring at least once in 93% of the
NPH-treated patients and 97% of the insulin glargine–treated
patients. Overall, adverse effects and injection site reac-
tions were comparable.
A similar study
6
performed in Europe compared 2 insulin
glargine formulations with NPH insulin in 333 patients
with type 1 diabetes previously treated with a basal-bolus
regimen. As in the other study, patients received premeal
regular human insulin plus either insulin glargine (contain-
ing 30 or 80 µg/mL of zinc) once daily at bedtime or NPH
insulin once daily at bedtime or twice daily in the morning
and at bedtime according to their prestudy regimen. After
4 weeks of therapy, the fasting plasma glucose was re-
duced 40 mg/dL from baseline in the insulin glargine (30
µg/mL of zinc) group (p = 0.0002) and was unchanged in
the NPH group. HbA
1C
was reduced 0.25% in patients re-
ceiving insulin glargine (30 µg/mL of zinc, p = 0.0001),
but was unchanged in the NPH group. The overall fre-
quency of hypoglycemia was comparable between the
groups, but nocturnal hypoglycemia occurred less frequently
in the insulin glargine group than in the NPH once-daily
group (36% vs. 56%, respectively; p = 0.0037).
TYPE 2 DIABETES
Several studies have also evaluated insulin glargine in
comparison with NPH insulin in patients with type 2 dia-
betes mellitus. Trials have included patients not controlled
with oral antidiabetic agents, as well as patients previously
receiving insulin therapy. Results from these studies are
summarized in Table 1.
Insulin glargine and NPH insulin administered in con-
junction with oral antidiabetic agents were evaluated in a
52-week study
1,25
enrolling 570 patients with type 2 dia-
betes. Patients received either insulin glargine once daily at
bedtime or NPH insulin once daily at bedtime for 52 weeks
in addition to oral antidiabetic agents (a sulfonylurea alone,
metformin alone, or a sulfonylurea plus metformin or acar-
bose). The insulin dose was titrated to achieve a fasting
blood glucose concentration of ≤120 mg/dL. HbA
1C
and
fasting blood glucose concentration declined in both the
insulin glargine and NPH groups. The total insulin dose in-
creased in both groups (11.5 units with insulin glargine and
9 units with NPH). Rates of hypoglycemia were similar in
the 2 groups. Results from a subset of 426 insulin-naïve
patients enrolled in this study have also been reported.
25,32
The average daily insulin dose at 1 year was 23 units in the
insulin glargine group and 21 units in the NPH group.
HbA
1C
was reduced to a similar extent in both groups, de-
clining by 0.76% in patients receiving insulin glargine (p <
0.001 vs. baseline) and by 0.66% in those on NPH insulin
(p < 0.001 vs. baseline). Glucose concentrations after din-
ner were lower with insulin glargine (178 vs. 193 mg/dL; p
< 0.02). Glucose concentrations at 0300 were lower in the
NPH-treated patients. Nocturnal hypoglycemia occurred
less frequently in the insulin glargine group (9% vs. 21.4%;
p = 0.012).
In an open-label trial,
1,26
insulin glargine was compared
with NPH insulin in 518 patients with type 2 diabetes pre-
viously treated with insulin. Insulin doses were adjusted to
achieve a target fasting glucose concentration of 80–140
mg/dL. Compared with the basal insulin dose prior to study
initiation, the dose of basal insulin decreased by 1.2 units
in the insulin glargine group, but was increased by 7 units
in the NPH insulin group. The dose of regular insulin was
increased in both groups. The median total daily insulin
dose in both groups was 0.75 units/kg at study endpoint.
HbA
1C
and fasting blood glucose concentrations were re-
duced to a similar extent in both groups. A fasting blood
glucose concentration <120 mg/dL was achieved in 29.6%
of insulin glargine–treated patients and 27.1% of NPH in-
sulin–treated patients by the study’s end. Weight gain was
greater in the NPH group (1.4 vs. 0.4 kg; p < 0.0007). The
overall incidence of symptomatic hypoglycemia was simi-
lar in the 2 groups (61.4% with insulin glargine; 66.8%
with NPH insulin); however, nocturnal hypoglycemia oc-
curred less frequently in the insulin glargine group (31.3%
vs. 40.2%; p < 0.02).
Insulin glargine has also been compared with once-daily
NPH insulin in a study
27
enrolling 100 patients with type 2
diabetes previously treated with once-daily NPH. Similar
reductions in HbA
1C
and fasting blood glucose concentra-
tions were observed in the 2 treatment groups, and a simi-
lar percentage of patients in each group achieved target
HbA
1C
concentrations. Symptomatic hypoglycemia was
Insulin Glargine: A New Basal Insulin
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reported by 46.2% of insulin glargine–treated patients
compared with 60.4% of NPH-treated patients (p = 0.0488).
A symptomatic hypoglycemic event with a blood glucose
concentration <50 mg/dL occurred in 17.3% of patients re-
ceiving insulin glargine compared with 31.3% of those on
NPH insulin (p = 0.0017). Symptomatic nocturnal hypo-
glycemia occurred in 15.4% with insulin glargine and 27.1%
with NPH insulin; the difference was not statistically sig-
nificant.
Insulin glargine was compared with NPH insulin in 157
patients with type 2 diabetes inadequately controlled with
a maximal dose of a sulfonylurea or a sulfonylurea plus
metformin.
33
The oral agents were discontinued, and in-
sulin glargine (30 or 80 µg/mL of zinc) or NPH insulin
was given once daily at bedtime and individually titrated.
Therapy was continued for 4 weeks. There was no differ-
ence between therapies in fasting plasma glucose, fruc-
tosamine, HbA
1C
concentrations, or the frequency of hypo-
glycemia. Fasting plasma glucose was reduced by 47–50
mg/dL in the insulin glargine groups and by 41 mg/dL in
the NPH insulin group.
The same 2 formulations of insulin glargine were evalu-
ated
34
in comparison with NPH insulin as an adjunct to
therapy in 204 patients with type 2 diabetes moderately
controlled with a sulfonylurea alone or in combination
with metformin or acarbose. There was no difference in
glycemic control between the treatment groups. HbA
1C
was
reduced by 0.8% from baseline in all 3 groups (p < 0.0001).
Hypoglycemia occurred in 7.3% of insulin glargine–treat-
ed patients compared with 19.1% of NPH-treated patients
(p < 0.037).
Adverse Effects and Drug Interactions
The adverse effects of insulin glargine are typical of those
of insulin including hypoglycemia, injection site reactions,
lipodystrophy, allergic reactions, pruritus, and rash.
1,2,6,23,26
Because it is an acidic solution, insulin glargine causes
more pain than NPH insulin at the injection site.
1,21,23,26
In
one study
23
comparing insulin glargine with NPH insulin,
injection site pain was reported for 6.1% of patients in the
insulin glargine group compared with 0.3% of patients in
the NPH insulin group. Injection site pain was generally
described as mild and did not result in discontinuation of
therapy.
21,23,26
The incidence of hypoglycemia is similar to
or slightly lower than that of NPH insulin, although insulin
glargine may be associated with less nocturnal hypo-
glycemia than once-daily NPH insulin.
6,18,21,26,28
The symp-
toms associated with the hypoglycemia induced by insulin
glargine are similar to those observed with regular human
insulin. There is no difference in the counter-regulatory
hormones during hypoglycemia induced by insulin glargine
and human regular insulin.
35,36
In one clinical trial, progression of retinopathy, defined as
a >3-step progression based on a photographic grading pro-
tocol derived from the Early Treatment Diabetic Retinopa-
thy Study, occurred more frequently with insulin glargine
therapy (7.5%) than NPH therapy (2.7%) over a 6-month
period in patients with type 2 diabetes. The relevance of
this finding is unknown and will continue to be assessed
during the Phase IV development of insulin glargine.
1
No
difference in retinopathy progression was observed in a
small 28-week study
37
comparing NPH insulin and insulin
glargine in 20 patients with type 1 diabetes. Retinopathy
grades (Modified Airlie House Classification) increased
from 2.4 to 2.7 in the NPH insulin group and from 2.9 to
3.3 in the insulin glargine group. Neither the changes from
baseline to last visit nor the differences between the groups
were significant.
The warnings and precautions associated with the use of
insulin glargine are similar to those of NPH insulin and regu-
lar human insulin and include hypoglycemia, hypokalemia,
lipodystrophy, hypersensitivity, renal impairment, and hep-
atic impairment. Insulin glargine is contraindicated in pa-
tients sensitive to it or any of the product excipients (zinc,
m-cresol, glycerol 85%).
1
Currently, the only interactions associated with insulin
glargine are with medications that may increase or de-
crease insulin requirements. Insulin requirements may be
increased by concurrent administration of medications
known to increase blood glucose concentrations such as
corticosteroids, danazol, diuretics, isoniazid, niacin, estro-
gens, oral contraceptives, phenothiazines, sympathomimet-
ics (e.g., epinephrine, albuterol, terbutaline), somatotropin,
and thyroid replacement therapy. Insulin requirements may
be reduced by medications known to produce hypoglycemia
such as oral hypoglycemic medications, disopyramide, fi-
brates, fluoxetine, salicylates, propoxyphene, sulfonamide
antibiotics, pentamidine, monoamine oxidase inhibitors,
angiotensin-converting enzyme inhibitors, β-blockers, and
octreotide. β-Blockers, clonidine, lithium salts, pentami-
dine, and alcohol may increase or decrease the blood glu-
cose–lowering effect of insulin.
1
Special Populations
The safety and efficacy of insulin glargine did not differ
in geriatric patients from that observed in younger patients.
As with other insulins, insulin glargine should be dosed
conservatively in elderly patients. Safety and effectiveness
have been established in children ≥6 years old.
1
Insulin glargine is in pregnancy category C. Effects in
animal studies were generally comparable with those ob-
served with regular human insulin, although at high doses
in rabbits, dilation of the cerebral ventricles was observed.
Fertility and early embryonic development appeared nor-
mal. It is not known whether insulin glargine is excreted in
significant quantities in human milk.
1
Pharmacoeconomics
Pharmacoeconomic studies comparing insulin glargine
with other intermediate- or long-acting insulins used as
basal insulin therapy have not been performed. Such trials
would need to compare the direct medication costs as well
as costs associated with adverse effects, particularly hypo-
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TL Levien et al.

glycemia. In addition, because insulin glargine cannot be
mixed with other insulins, the costs associated with sepa-
rate injections of insulin glargine and regular human in-
sulin must be considered.
Currently, the cost to the patient of insulin glargine at 2
popular Internet pharmacy sites ranges from $43.95 to
$48.99 for the 10-mL vial.
38,39
In comparison, NPH insulin
(Humulin N, Novolin N) could be purchased for $22.53–
25.99 per 10-mL vial.
Dosage and Administration
Insulin glargine is administered as a subcutaneous injec-
tion once daily at bedtime. The site of injection should be
the abdomen, deltoid, or thigh. The prolonged duration of
activity of the formulation depends on subcutaneous ad-
ministration. Insulin glargine solution should not be ad-
ministered intravenously, as the usual subcutaneous dose
could result in severe hypoglycemia.
1
In patients with type 2 diabetes not currently receiving
insulin, insulin glargine therapy has been initiated at an av-
erage dose of 10 units once daily and subsequently titrated
to daily doses ranging from 2 to 100 units.
1
In patients cur-
rently receiving once-daily NPH or ultralente insulin, in-
sulin glargine can be initiated at the same daily dose. To
decrease the risk of hypoglycemia, caution should be used
when switching from twice-daily NPH insulin to once-
daily insulin glargine. For patients switching from twice-
daily NPH insulin, the initial daily dose of insulin glargine
should be reduced by approximately 20% compared with
the total daily NPH insulin dose and then titrated based on
patient response.
Insulin glargine must not be diluted or mixed with any
other insulin or solution.
1
When diluted or mixed, the solu-
tion may become cloudy and the pharmacokinetic/pharma-
codynamic profile of either product may be altered. Be-
cause insulin glargine is formulated as an acidic solution, it
cannot be mixed with insulin formulated at a neutral pH,
such as regular insulin.
40
When insulin glargine and regular
human insulin were mixed immediately prior to adminis-
tration in dogs, a delayed onset of action and delayed time
to maximum effect of regular human insulin were ob-
served. The total bioavailability of the mixture was also re-
duced compared with separate administration of each com-
ponent.
1,40
Unopened vials and cartridges of insulin glargine should
be stored in the refrigerator (2–8 ºC) and protected from
freezing. If refrigeration is not possible, the 10-mL vial or
the cartridge in use can be kept unrefrigerated for up to 28
days and thereafter discarded. Once the cartridge has been
placed within the insulin delivery device, it should not be
refrigerated. The opened 5-mL vial can be kept unrefriger-
ated for up to 14 days, but must be used within that period
or discarded. If refrigerated, the 5-mL vial in use can be
kept for up to 28 days. Unrefrigerated vials and cartridges
must be stored away from direct heat and light at tempera-
tures not exceeding 30 ºC.
1
Patient Counseling
Unlike other intermediate- and long-acting insulins, in-
sulin glargine is a clear, colorless solution. Patients should
be informed of this difference. In the past, patients have of-
ten been instructed in mixing insulins in terms of mixing
the clear and the cloudy insulins; however, they now must
understand that, although clear, insulin glargine cannot be
mixed with other insulins. In addition, unlike other inter-
mediate- and long-acting insulins, insulin glargine does not
need to be shaken.
Patients should be advised that they may experience
pain on injection due to the acidic pH of the solution. Pa-
tients may be more accepting of this adverse effect if it
does not come as a surprise.
Blood glucose concentrations should be closely moni-
tored in all patients receiving insulin therapy, and instruc-
tion on monitoring should be provided if necessary. Pa-
tients should be closely monitored during the initial weeks
of insulin glargine therapy to adjust doses of insulin glargine,
short-acting insulin, and/or oral antidiabetic agents. Period-
ic determination of HbA
1C
is recommended for monitoring
long-term glycemic control.
Patients and healthcare professionals should be cau-
tioned regarding the similarity of the name Lantus with
Lente. At least 1 error has been reported
41
due to the simi-
larity of the names of these insulin products.
Formulary Recommendation
Insulin glargine offers some advantages over existing
agents used for basal insulin therapy with its once-daily ad-
ministration, a continuous plateau of serum concentrations,
24-hour duration of activity, and reduced incidence of noc-
turnal hypoglycemia. Disadvantages currently include in-
creased cost, increased pain on injection compared with
NPH insulin, and the inability to mix it with other insulins.
Summary
Insulin glargine is a long-acting insulin analog capable
of providing 24-hour basal insulin coverage without pro-
nounced peaks in insulin concentrations or activity. Struc-
tural modifications have created an insulin that is solubi-
lized in an acidic solution, but which crystallizes at the more
neutral pH of the subcutaneous tissue, forming a depot from
which the insulin is slowly released. Insulin glargine is ad-
ministered once daily at bedtime. It has demonstrated effi-
cacy comparable to that of NPH insulin administered once
or twice daily in basal-bolus regimens with intermittent
doses of regular insulin or insulin lispro in patients with
type 1 and type 2 diabetes and in conjunction with oral an-
tidiabetic agents in patients with type 2 diabetes. Overall,
insulin glargine has been associated with an incidence of
hypoglycemia comparable to or less than that of NPH in-
sulin. A reduced incidence of nocturnal hypoglycemia
compared with NPH insulin has been observed in a num-
ber of studies.
Insulin Glargine: A New Basal Insulin
The Annals of Pharmacotherapy
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2002 June, Volume 36
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Terri L Levien PharmD, Drug Information Pharmacist, College of
Pharmacy, Washington State University Spokane, Spokane, WA
Danial E Baker PharmD FASCP FASHP, Director, Drug Informa-
tion Center, Professor of Pharmacy Practice, College of Pharmacy,
Washington State University Spokane
John R White Jr PA-C PharmD, Associate Professor of Pharma-
cy Practice, College of Pharmacy, Washington State University
Spokane
R Keith Campbell BPharm MBA CDE FASHP FAPhA, Associate
Dean; Professor of Pharmacy Practice, College of Pharmacy, Wash-
ington State University, Pullman, WA
Reprints: Terri L Levien PharmD, College of Pharmacy, Washing-
ton State University Spokane, Health Sciences Bldg., 210N, 310 N.
Riverpoint Blvd., Box S, Spokane, WA 99202-1675, FAX 509/358-
7744, E-mail levient@wsu.edu
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EXTRACTO
OBJETIVO: Repasar la farmacología, farmacocinética, guías de
dosificación, efectos adversos, interacciones de fármacos, y eficacia
clínica de la insulina glargina.
FUENTES DE INFORMACIÓN: Articulos primarios y de revisión con relación
a la insulina glargina fueron identificados a través de una búsqueda en
MEDLINE (del 1966–julio 2001); se identificaron extractos a través de
la Asociación Americana de Diabetes y del Instituto para la Información
Científica Red de Ciencia (del 1995–julio 2001). Información adicional
fue obtenida de la información del producto de insulina glargina.
SELECCIÓN DE FUENTES DE INFORMACIÓN Y MÉTODO DE EXTRACCIÓN DE
INFORMACIÓN:
Todos los artículos y extractos de reuniones identificados
de las fuentes de información fueron evaluados, y toda la información
que se consideró relevante fue incluída en este repaso. Se dió prioridad a
datos identificados en la literatura médica primaria.
SÍINTESIS: La insulina glargina es un análogo, de acción prolongada, de la
insulina humana recombinante, que se administra 1 vez al día como una
fuente basal de insulina en pacientes con diabetes mellitus tipo 1 ó tipo
2. La modificación de la estructura básica de insulina ha producido una
nueva insulina, soluble a un pH acídico, que se precipita en tejidos
subcutáneos y se libera lentamente de un depósito. La insulina glargina
tiene un comienzo de acción más lento que la insulina NPH y una
duración de acción más prolongada, sin un pico. La administración
diaria de insulina glargina tiene una eficacia comparable a la insulina
NPH administrada 1 o 2 veces al día, en regimenes de bolo basal cuando
se utiliza en combinación con dosis intermitentes de insulina regular o
insulina lispro en pacientes con diabetes tipo 1 y tipo 2, y en conjunto
con agentes antidiabéticos orales en pacientes con diabetes tipo 2. En
general, la insulina glargina tiene una incidencia de hipoglicemia
comparable o menor que la de insulina NPH, con una incidencia de
hipoglicemia nocturna reducida comparada con la que se ha visto con
insulina NPH en algunos estudios. Fisiológicamente, la insulina glargina
provee insulina basal, pero para la gran mayoría de los pacientes, la
adición de una insulina de acción rápida como insulina lispro antes o
con las comidas tendrá que ser incluída en el régimen de tratamiento
para alcanzar el manejo óptimo de los niveles de glucose en sangre.
CONCLUSIONES: La insulina glargina es un análogo de insulina, de acción
prolongada, capaz de proveer una cubierta de insulina basal por 24 horas
al administrarse 1 vez al día, al acostarse. Su perfil de actividad, que
carece de un pico pronunciado, se asemeja más a la insulina basal
endógena que otras insulinas de acción intermedia o de acción
prolongada, y parece estar asociada en menor grado con hipoglicemia
nocturna.
Brenda R Morand
RÉSUMÉ
OBJECTIF: Revoir la pharmacologie, la pharmacocinétique, les dosages
recommandés, les effets indésirables, les interactions médicamenteuses,
et l’efficacité clinique de l’insuline glargine.
REVUE DE LITTÉRATURE: Une recherche de type MEDLINE (de 1966 à
juillet 2001) a permis d’identifier des articles originaux et de revue sur
l’insuline glargine; des résumés furent identifiés en consultant le
Institute for Scientific Information Web of Science (de 1995 à juillet
2001) et l’Association diabétique américaine; des informations
supplémentaires furent obtenues dans l’information du produit de
l’insuline glargine.
SÉLECTION DES ÉTUDES ET DE L’INFORMATION: Tous les articles et les
résumés de conférences identifiés furent évalués et toute l’information
pertinente fut inclue dans cet article. Les données provenant d’articles
originaux furent priorisées.
RÉSUMÉ: L’insuline glargine est une insuline analogue humaine
recombinante longue action qui se donne une fois par jour comme
source basale d’insuline aux diabétiques de type 1 ou 2. La modification
de la structure de base de l’insuline a produit une nouvelle insuline qui
est soluble dans un pH acide mais qui précipite dans le tissu sous-cutané
et qui par conséquent se libère graduellement du dépot ainsi formé.
L’insuline glargine a un début d’action plus lent que l’insuline NPH et
une durée d’action plus longue, sans pic. L’administration
uniquotidienne de l’insuline glargine donne une efficacité comparable à
l’insuline NPH administrée 1 à 2 fois par jour dans des thérapies
basales-bolus lorsque utilisée en association avec des doses
intermittentes d’insuline régulière ou d’insuline lispro chez des
diabétiques de type 1 ou 2 et en association avec des hypoglycémiants
oraux chez les diabétiques de type 2. Globalement, l’insuline glargine
possède une incidence d’hypoglycémies comparable ou inférieure à
l’insuline NPH avec une incidence réduite d’hypoglycémies nocturnes
comparativement à l’insuline NPH tel que décrit dans la littérature.
Physiologiquement, l’insuline glargine fournit une insuline basale mais
pour la plupart des patients l’addition d’une insuline à action rapide,
comme l’insuline lispro avant ou avec les repas, sera nécessaire pour
obtenir un contrôle optimal de la glycémie.
CONCLUSIONS: L’insuline glargine est une insuline à longue action
capable de fournir des taux de base d’insuline pendant 24 heures avec
une administration monoquotidienne au coucher. Elle possède un profil
d’activité, sans pic prononcé, qui ressemble plus à l’insuline basale
endogène que les autres insulines de type intermédiaire ou longue action
et semble moins sujette à provoquer des hypoglycémies nocturnes.
Pierre Dion
Insulin Glargine: A New Basal Insulin
The Annals of Pharmacotherapy
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2002 June, Volume 36
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1027
www.theannals.com