F E A T U R E A R T I C L E

Volume 21, Number 1, 2003CLINICAL DIABETES

14
Clarifying the Role of Insulin in
Type 2 Diabetes Management
John R. White, Jr., PA-C, PharmD; Stephen N. Davis, MD, FRCP; Ramachandiran Cooppan, MD; Mayer B. Davidson, MD;
Kathryn Mulcahy, RN, MSN, CDE; Gary A. Manko, MD; Donald Nelinson, PhD; and the Diabetes Consortium Medical
Advisory Board
D
iabetes is a highly prevalent
chronic disease. The Third
National Health and Nutrition
Examination Survey, conducted between
1988 and 1994, estimated the prevalence
of diagnosed and undiagnosed diabetes
in people aged 20 years and older at
15.6 million.
1
Of these people, ~9095%
have type 2 diabetes, with a higher
prevalence seen among Native
Americans and Americans of African,
Mexican, and Japanese descent.
2
The
prevalence of diabetes rose from 4.9%
in 1990 to 6.9% in 1999, primarily
because of an increase in the prevalence
of obesity. It has been postulated that,
with the growing obesity problem, dia-
betes will become an even more perva-
sive threat.
3
Type 2 diabetes produces or is a con-
tributor to considerable morbidity in the
form of metabolic complications, vision
disorders, neuropathy, kidney disease,
peripheral vascular disease, ulcerations
and amputations, heart disease, stroke,
digestive diseases, infection, oral com-
plications, and depression. The associat-
ed mortality rate has been estimated at
5.5% annually. Moreover, the disease
reduces life expectancy by 510 years.
1
Although there is no cure for dia-
betes, two large controlled studies, the
Diabetes Control and Complications Tri-
al (DCCT)
4
and the U.K. Prospective
Diabetes Study (UKPDS)
5
have pointed
to the importance of intensive blood glu-
cose control in reducing its associated
morbidity. In fact, the UKPDS, the
largest and longest trial ever conducted
in patients with type 2 diabetes, found
that for each 1% reduction in hemoglo-
bin A
1c
(A1C), there was a 21% decrease
in any endpoint related to diabetes and in
diabetes-related death, a 14% decrease in
all-cause mortality and myocardial
infarction, a 43% decrease in amputation
or death from peripheral vascular dis-
ease, and a 37% decreased risk for
microvascular complications, each of
which was statistically significant.
5
The
Japanese Kumamoto study
6
also found
that intensive glycemic control reduced
the risk for retinopathy, nephropathy, and
neuropathy in patients with type 2 dia-
betes.
Although sulfonylurea therapy has
been the mainstay of treatment for type 2
diabetes for >40 years, the UKPDS
reported that over a 6-year period, ~53%
of patients who were randomized to
receive treatment with sulfonylureas
needed additional insulin therapy, rein-
forcing the concept that hyperglycemia
in type 2 diabetes is progressive.
7
Clini-
cians should consider this when estab-
lishing a therapeutic regimen for patients
with type 2 diabetes.
This article addresses the pathophys-
iology of type 2 diabetes, goals of thera-
py, misconceptions about insulin,
restoration of natural insulin patterns,
and ways to incorporate basal insulin
into a strategy that promotes compliance.
Pathophysiology of Type 2 Diabetes
Type 2 diabetes is characterized by
hyperglycemia caused by defects in
insulin secretion (impaired -cell func-
tion) and insulin action (insulin resist-
ance by the liver and muscle tissue).
810
These defects occur early in the course
of the disease and are often present
before diagnosis.
In a prospective study
11
of Pima Indi-
ans, a group at high risk for developing
diabetes, body composition, insulin
action, insulin secretion, and endogenous
glucose output were measured over sev-
eral years in subjects whose glucose tol-
erance went from normal to impaired to
diabetic. A two-step hyperinsulinemic,
euglycemic glucose clamp test assessed
insulin action. During the transition from
normal to impaired glucose tolerance,
there was a 27% decrease in the acute
insulin secretory response (AIR), the
average incremental plasma insulin con-
centration from the third to the fifth
minute after the glucose bolus. Further-
more, during the transition from
impaired glucose tolerance to diabetes,
there was an additional 57% decrease in
AIR.
Another controlled study in patients
with type 2 diabetes who were either
untreated or attempting to achieve con-
trol using diet or oral hypoglycemic
agents
9
found that basal and mean 24-
hour glucose concentrations were signif-
The prevalence of type 2 diabetes has
been increasing rapidly and with it
has been resultant morbidity and mor-
tality. Strict glycemic control reduces
the progression of diabetic microvas-
cular disease; however, most patients
treated with sulfonylureas require
additional insulin therapy. This article
addresses common clinician concerns
about prescribing insulin early in type
2 diabetes. It presents strategies for
incorporating basal insulin therapy
with glargine (Lantus) into a regimen
that promotes compliance.
I N BRI EF
F E A T U R E A R T I C L E
15
CLINICAL DIABETESVolume 21, Number 1, 2003
immune-mediated -cell destruction that
is characteristic of type 1 diabetes. This
disease, latent autoimmune diabetes of
adulthood, is often treated in the same
way as type 2 diabetes because it does
not require insulin initially.
13
Therapeutic Objective
The American Diabetes Association
(ADA) recommends that patients with
diabetes receive care from a medical
team. Working with patients and their
families, these teams develop self-man-
agement and problem-solving plans that
consider each patients cultural, social,
physical, and medical needs. ADA sup-
ports the findings of the DCCT and the
UKPDS for intensive glycemic control;
Table 2 lists its recommendations for
nonpregnant people with diabetes.
14
Insulin: Misconceptions and Reality
Contrary to some beliefs, there is no
evidence that doses of insulin used in
clinical practice exacerbate insulin
resistance. It has long been recognized
that the chronic hyperglycemia associ-
ated with type 2 diabetes (glucose toxi-
city) leads to impairment in insulin
secretion and a possible defect in glyco-
gen synthesis.
15
In a study of intensive
insulin therapy in patients with type 2
icantly higher in the diabetic patients,
pointing to potentially impaired insulin
secretion. During the hyperglycemic
clamp portion of this study, patients
secreted ~70% less insulin than control
subjects (Table 1). In nondiabetic indi-
viduals, a biphasic insulin response
begins upon glucose stimulation, starting
with a rapid rise in insulin 13 minutes
after the glucose level is raised (first
phase), returning toward baseline 610
minutes after glucose stimulation, and
rising gradually once again (second
phase).
12
Among patients in this study,
however, the first-phase response after
meals (glycemic load) was either absent
or greatly diminished.
9
As a result of
bolus (mealtime) and basal (between-
meal) defects in insulin activity in type 2
diabetes, bolus and basal glucose levels
are increased, producing hyperglycemia.
In the early stages of type 2 diabetes,
blood glucose levels can often be con-
trolled with changes in diet and physical
activity along with sulfonylureas. Unfor-
tunately, the -cell dysfunction that
leads to impaired insulin secretion is
progressive, and eventually patients will
require a treatment strategy that includes
insulin, either alone or with oral agents.
7
It should be noted that some patients
who develop diabetes in adulthood have
diabetes,
16
the use of insulin partially
reversed the postbinding defect in
peripheral insulin action, produced
near-normal basal hepatic glucose out-
put, and enhanced insulin secretion,
thereby maintaining lower glucose val-
ues. In addition, the mean daily insulin
requirement fell by 23% after ~2 weeks
of therapy, leveling off thereafter.
The use of insulin has been associat-
ed with weight gain, which in turn has
been considered a major factor in insulin
resistance. In the UKPDS, patients in
intensive therapy gained more weight
than those in conventional therapy
groups; patients taking insulin gained ~4
kg compared to 2.6 kg for those on
chlorpropamide (Diabinese) and 1.7 kg
for those on glibenclamide (glyburide
[Micronase]).
17
Yet patients in the inten-
sive therapy groups also had fewer
microvascular complications, suggesting
that tight glycemic control may be more
important in therapeutic decision-mak-
ing. The use of metformin (Glucophage)
as an adjunct to insulin therapy provides
effective glycemic control without sig-
nificant weight gain.
18,19
The incidence of heart disease and
ischemic heart mortality is up to four
times higher in people with diabetes.
Ischemic heart disease, other heart dis-
ease, and cerebrovascular disease
account for 40, 15, and 10% of all deaths
in this population, respectively (Figure
1).
20
A population-based survey of
almost 3,000 people
21
identified high
prevalence rates for a constellation of
disorders known as syndrome X, meta-
bolic syndrome, and insulin resistance
syndrome interchangeablyabdominal
obesity, type 2 diabetes, glucose intoler-
ance, hypertension, hypertriglyc-
eridemia, and hypercholesterolemia
that far exceeded the rates for each
disorder alone or in pairs. For each of
these conditions, fasting and post-glu-
cose hyperinsulinemia was a common
thread that suggested the presence of
insulin resistance. When insulin-resistant
subjects were compared to control sub-
jects, significantly lower HDL choles-
terol levels were also seen.
Table 1. Glucose Concentrations and Insulin Secretion in Control and
Diabetic Subjects Under Three Conditions
Condition Control Patients With P
Subjects Diabetes
Fasting
Glucose (mg/dl) 95.2 2.1 221.4 19.4 <0.0001
Insulin secretion
(nmol/m
2
/24 hours) 71.7 9.5 82.7 11.5 NS
24-Hour Study
Glucose (mg/dl) 109.7 1.9 282.3 25.6 <0.0001
Insulin secretion
(nmol/m
2
/24 hours) 220.5 30.4 201.7 19.7 NS
Hyperglycemic Clamp Study
Glucose (mg/dl) 303.6 4.5 299.8 1.0 NS
Insulin secretion
(nmol/m
2
/24 hours) 80.6 11.7 24.1 4.1 <0.001
Adapted with permission from Ref. 9.
F E A T U R E A R T I C L E
Volume 21, Number 1, 2003CLINICAL DIABETES
16
years; the absolute reduction in mortali-
ty was 11%.
23
Other studies
2426
have reported
improvement or neutral effects on other
cardiovascular risk factorstotal choles-
terol, LDL cholesterol, HDL cholesterol,
triglycerides, or hypertensionwith
insulin, even among obese patients.
Considering the comorbidity of dia-
Because of the connection among
hyperinsulinemia, insulin resistance, and
cardiovascular risk factors, the UKPDS
17
compared cardiovascular events among
patients randomized to conventional
lifestyle and dietary management and
those on a tight glycemic control regi-
men with sulfonylureas, metformin (in
overweight patients), or insulin. No
adverse effects on cardiovascular out-
comes were seen with any of the treat-
ments, including insulin.
The Diabetes Mellitus Insulin Glu-
cose Infusion in Acute Myocardial
Infarction study
22,23
assessed the effect
of acute insulin-glucose infusion fol-
lowed by long-term intensive (multi-
dose) insulin treatment in diabetic
patients who have had an acute
myocardial infarction. Among patients
who had received an acute infusion,
there was a significant decrease in glu-
cose. After 1 year, there was a signifi-
cant reduction in mortality in the group
who received intensive insulin treat-
ment, particularly in patients who had a
low cardiovascular risk profile and
were insulin naive.
22
These effects per-
sisted after a mean follow-up of 3.4
betes and several cardiovascular risk fac-
tors, ADA
14
recommends the following
in addition to lifestyle alterations: blood
pressure measurement at routine medical
visits; the use of antihypertensive agents
in patients with hypertension; testing for
lipid disorders at least annually; lower-
ing LDL and triglycerides; increasing
HDL and using statins as first-line lipid
therapy; using fibrates in patients with
low HDL; and using aspirin therapy to
prevent cardiovascular events.
Clinicians often cite hypoglycemia
as an adverse effect that might preclude
the use of insulin. Indeed, in the DCCT
study of type 1 diabetes,
4
tighter control
produced a risk of severe hypoglycemia
three times higher than that of conven-
tional therapy (Figure 2). This must be
viewed, however, in the context of sub-
stantially reduced microvascular and
neurological complications. Further-
more, the rates of severe hypoglycemia
are quite low in type 2 diabetes. In the
Kumamoto study of type 2 diabetes,
6
average A1C results were 7.1 and 9.4%
for tight and conventional groups,
respectively. However, only mild hypo-
glycemic reactions occurred and at simi-
lar rates in both groups.
The UKPDS
17
found that the rate of
major hypoglycemic episodes (defined
as an episode in which help from another
Table 2. ADA Guidelines for Glycemic Control for Patients With Diabetes
Normal Goal Additional action
suggested
*
Plasma values (mg/dl)

Average preprandial glucose <110 90130 <90/>150

Average bedtime glucose <120 110150 <110/>180
Whole blood values (mg/dl)

Average preprandial glucose <100 80120 <80/>140

Average bedtime glucose <110 100140 <100/>160
A1C <6 <7 >8
The values shown in this table are by necessity generalized to the entire population of individuals
with diabetes. Patients with comorbid diseases, the very young and older adults, and others with
unusual conditions or circumstances may warrant different treatment goals. These values are for non-
pregnant adults.
*Values above/below these levels are not goals nor are they acceptable in most patients. They are
an indication for a significant change in the treatment plan. Additional action suggested depends on
individual patient circumstances. Such actions may include enhanced diabetes self-management edu-
cation, comanagement with a diabetes team, referral to an endocrinologist, change in pharmacologi-
cal therapy, initiation of or increase in self-monitoring of blood glucose, or more frequent contact
with the patient. A1C is referenced to a nondiabetic range of 4.06.0% (mean 5.0%, SD 5%).
Values calibrated to plasma glucose.
Measurement of capillary blood glucose.
Reprinted with permission from Ref. 14.
13%
13%
4%
5%
65%
40%
15%
10%
Diabetes
Malignant neoplasms
Pneumonia/influenza
All other
Ischemic heart disease
Other heart disease
Cerebrovascular disease
Figure 1. Cardiovascular and cerebrovascular diseases account for 65% of all
deaths in patients with diabetes. Adapted from Ref. 20.
F E A T U R E A R T I C L E
17
CLINICAL DIABETESVolume 21, Number 1, 2003
concentration that result from the inges-
tion of food. In people with diabetes,
however, bolus and basal glucose levels
are increased; thus, strategies for insulin
replacement must focus on mimicking
the phases of insulin secretion. Figure 3
shows available insulins by onset, peak,
and usual effective duration.
27
Prandial (Bolus) Insulin
Prandial forms of insulin mimic the nor-
mal first-phase response. These regular
insulin or rapid-acting insulin analogs
are administered 3060 minutes (regu-
lar) or 1015 minutes (lispro [Humalog]
or aspart [Novolog]) before food con-
sumption. They must also mimic the
second-phase response, requiring a more
prolonged duration of action to control
prolonged glucose elevation after the
meal.
28
Although prandial forms offer
flexibility in that they can be injected
just before a meal, most patients also
require daily basal insulin injections.
29
Basal Insulin
Both intermediate (NPH and lente) and
long-acting (ultralente and glargine
[Lantus]) insulins have been used to
person or medical intervention was nec-
essary) was higher for patients taking
insulin (2.3%) than for patients undergo-
ing any other intensive therapy or con-
ventional treatment (<1%). The rate of
any hypoglycemic episode (including
episodes that the patient was able to treat
unaided) was 36.5% with insulin treat-
ment, compared to 11, 17.7, and 1.2%
for chlorpropamide, glibenclamide, and
diet, respectively. In a secondary analy-
sis of obese patients on intensive
glycemic control, the rate of major hypo-
glycemic events per year for intensive
insulin treatment was 2.5% versus <1%
for other treatments.
Despite the increased risk of mild
hypoglycemia, aggressive therapy that
combines patient education and self-
management with a form of exogenous
insulin that closely mimics normal
insulin secretion can help to reduce the
morbidity and mortality associated with
type 2 diabetes.
Restoring Natural Insulin Patterns
Nondiabetic pancreases self-regulate the
amount of insulin secreted, acting in
response to changes in blood glucose
mimic physiological basal insulin secre-
tion, with varying results. An insulin that
mimics basal secretion should be slowly
and evenly absorbed with no peak, have
consistent bioavailability, and have a
long half-life that permits once-daily
administration.
30,31
This has not been the
case with most basal insulin products.
NPH and lente have early peaks with
rapid waning of action; this may con-
tribute to both nighttime hypoglycemia
and the dawn phenomenon, a pre-
breakfast rise in plasma glucose. There
is also variability in the absorption of
NPH and lente.
29,32
Data on ultralente
vary; in one study of type 1 diabetes,
30
the onset of action of human ultralente
was 24 hours, and there was a broad,
variable peak 612 hours after injection.
The authors concluded that this product
did not provide a constant basal insulin
concentration.
Basal insulin in type 1 diabetes. The
pharmacokinetics and pharmacodynam-
ics of the insulin analog glargine were
compared to those of NPH, ultralente,
and continuous subcutaneous insulin
infusion (CSII) of lispro in 20 type 1 dia-
betic patients using an isoglycemic 24-
hour clamp.
33
Glargine was absorbed
slowly and produced no pronounced
peaks over a 24-hour period. Its onset of
action was ~1.5 hours, compared with
0.8 hours for NPH, 1 hour for ultralente,
and 0.5 hours for CSII. Its concentra-
tion/action profile was similar to CSII,
with lower intersubject variability than
with NPH and ultralente. These factors
make glargine an excellent choice for
basal insulin replacement.
In another study of type 1 diabetes,
34
256 patients were randomized to receive
NPH (once daily at bedtime or twice dai-
ly before breakfast and at bedtime) or
glargine once daily at bedtime. After 1
week and sustained throughout the 4-
week study, fasting plasma glucose was
significantly lower in the pooled glargine
groups than in the NPH group (165.6 vs.
203.4 mg/dl, respectively; P = 0.0001).
Patients who had been taking NPH twice
daily before the study were more likely
to demonstrate greater improvement if
Figure 2. Rate of severe hypoglycemia in patients receiving intensive therapy. As
tighter glycemic control is attained, the risk of severe hypoglycemia increases.
Points, which correspond to more than 400 patient-years, indicate crude rates
within deciles of the mean glycosylated hemoglobin (A1C) values during the
trial. Copyright 1988 Massachusetts Medical Society. All rights reserved.
Adapted with permission, 2002.
120
100
80
60
40
20
0
5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5
Glycosylated Hemoglobin (%)
R
a
t
e

o
f

S
e
v
e
r
e

H
y
p
o
g
l
y
c
e
m
i
a
(
p
e
r

1
0
0

p
a
t
i
e
n
t
-
y
e
a
r
s
)
F E A T U R E A R T I C L E
Volume 21, Number 1, 2003CLINICAL DIABETES
18
high- and low-dose NPH alone in
restoring glycemic control.
37
Combina-
tion therapy with an intermediate-acting
insulin at bedtime plus metformin was
superior to bedtime insulin plus gly-
buride and metformin, bedtime insulin
plus glyburide, and insulin twice daily
and produced no weight gain.
18
The
addition of evening NPH to existing
oral agents was similar in efficacy to
morning NPH plus an existing antidia-
betic agent, a two-injection regimen of
70/30 insulin, multiple injections, and
oral hypoglycemic agents alone; howev-
er, this regimen did not induce as much
weight gain and hyperinsulinemia.
38
Recent clinical trials suggest that
glargine provides basal insulin glycemic
control equal to that of NPH with less
risk of hypoglycemia. Glargine has been
evaluated in patients with type 2 diabetes
in a trial comprising 518 patients who
had been receiving NPH with or without
regular insulin for postprandial control.
39
This 28-week, multicenter, open-label
comparison of NPH once or twice daily
and glargine once daily at bedtime
reported similar decreases in A1C but a
lower risk of nocturnal hypoglycemia
with glargine compared with NPH (26.5
randomized to a glargine group than
were patients previously on once-daily
NPH. The longer duration of glargine
also provided a statistically significant
advantage in reducing the likelihood of
the dawn phenomenon.
Basal insulin in type 2 diabetes. The
management of type 2 diabetes has tradi-
tionally followed a stepped approach of
lifestyle changes, to oral agents, to com-
binations of oral agents, to insulin.
Along the way, however, complications
resulting from poor glycemic control
may occur, some of which might have
been reduced or possibly avoided with
the early introduction of insulin.
35
Many studies have evaluated how to
use insulin effectively for the treatment
of type 2 diabetes. Two- and four-dose
regimens of NPH improved glycemic
control but caused basal hyperinsuline-
mia.
36
The addition of 70/30 insulin (a
premixed formulation with 30% fast-
acting insulin and 70% intermediate-
acting insulin) before supper to
glimepiride (Amaryl) restored glycemic
control more quickly than did 70/30
insulin alone, without producing severe
hypoglycemia.
25
The addition of NPH
to glipizide (Glucotrol) was superior to
vs. 35.5%; P = 0.016). There was signifi-
cantly less weight gain with glargine
than with NPH (0.4 vs. 1.4 kg; P =
0.0007).
A 6-month, multicenter, random-
ized, open-label trial
40
compared the
addition of glargine or NPH to an oral
therapy regimen to restore glycemic
control to a target A1C 7% in 756
insulin-nave patients with type 2 dia-
betes. A1C results were lower in both
treatment groups and 7% in 58% of
patients. At the end of the study, the
mean glargine dose was higher than that
of NPH; however, symptomatic hypo-
glycemia rates, particularly nocturnal
hypoglycemia, were significantly lower
in the glargine group. Risk was reduced
by 21% for any incidence of hypo-
glycemia and by 42% for nocturnal
hypoglycemia (Table 3).
Other studies comparing glargine to
NPH at bedtime reported that similar
control was achieved with each agent;
however, there were significantly less
hypoglycemia
41
and significantly lower
postdinner glucose concentrations
42
with
glargine than with NPH. Among insulin-
naive patients and overweight patients
who had been taking oral agents with or
without insulin, significantly fewer
receiving glargine experienced nocturnal
hypoglycemia.
43
An Algorithm for Using Insulin
There is no single best way to initiate
insulin therapy in patients with type 2
diabetes in whom oral treatments no
longer maintain adequate control.
Clinicians should consider 10 units of
basal insulin at bedtime, supper, or in
the morning a safe, effective recommen-
dation for beginning insulin therapy.
This dose can then be titrated based on
how well a patient has met individual
glycemic goals as measured by fasting
blood glucose, postmeal glucose levels,
and self-monitoring of blood glucose. In
obese, insulin-resistant patients, a higher
starting dose may be safely used.
Figure 4
44
provides an algorithm that
includes recommendations for the use of
insulin therapy in type 2 diabetes.
Figure 3. The action of human insulins. Onset, peak, and usual effective dura-
tions vary among available insulins. In some reports, ultralente has demonstrat-
ed a peak concentration after several hours, followed by waning. Values shown
are the mean in each range. Adapted with permission from Ref. 27.
Glargine
Ultralente
Lente
NPH
Regular
Lispro
Aspart
Onset
Peak
Duration
0 2 4 6 8 10 12 14 16 18 20 22 24
Hours
F E A T U R E A R T I C L E
19
CLINICAL DIABETESVolume 21, Number 1, 2003
ance. In the management of diabetes,
this is more than a relationship between
the patient and a single providerit
includes an entire health care team.
Other factors also influence compli-
ance. On the patients side, the belief that
the benefits of therapy are worth the con-
sequences, a readiness to change, memo-
ry, communication skills, literacy level,
knowledge, competence, confidence,
skills, and a good support system work
together to influence the patients accept-
ance of therapy. On the teams side,
communication skills, the quality of
information and instructions, and a will-
ingness to identify and address barriers
Compliance
Patients with diabetes play an integral
role in any treatment strategy. Lifestyle
modification; goal setting; self moni-
toring; preventing, detecting, and treat-
ing acute complications; and using
medications correctly are all important
components in achieving glycemic
control.
45
This makes patient education
crucial, particularly when it comes to
dispelling myths about insulin therapy.
The content areas that must be clearly
established for patients are listed in
Table 4.
The relationship between health care
provider and patient is crucial to compli-
affect compliance. The regimen itself is
also a factor; if it is difficult, costly, or
has many side effects, compliance may
diminish.
4649
In the treatment of type 2 diabetes
with insulin, reluctance to inject oneself
and fear of weight gain or hypoglycemia
may hinder compliance.
35
Clinicians
need to explain to their patients that type
2 diabetes is progressive and that insulin
will probably have to be used at some
point; therefore, clinicians may need to
dispel myths associated with insulin use,
allay patient fears, and assure patients
that insulin will likely improve symp-
toms, enhance quality of life, and pro-
vide a sense of well-being.
Resistance to insulin on the part of
clinicians may also be a significant
provider-driven factor in compliance.
50
Concerns regarding hypoglycemia,
patients fear of needles, cultural health
beliefs, and the time necessary to teach
self-injection can all emerge as barriers
to insulin use.
Table 3. Relative Risk of Hypoglycemic Episodes per Patient-Year
Hypoglycemia Glargine NPH(%) P Relative Risk With
(%) Glargine (%)
All confirmed 13.9 17.7 <0.02 21
Nocturnal confirmed 4.0 6.9 <0.001 42
Adapted with permission from Ref. 40.
Test for diabetes
A1C 6.5% A1C >6.5%
A1C 6.5%
A1C >6.5%
Reassess for type 2 diabetes
MNT, physical activity,
risk factor reduction
Retest for diabetes
in 1 year
FPG 126140 mg/dl
Or A1C <6.5%
Continue therapy:
Reassess every 3 months
FPG 140160 mg/dl
or A1C 6.5%8.0%
Continue insulin
therapy
FPG >160 mg/dl
or A1C >8.0%
Assess for severe symptoms
(polydypsia, polyuria, weight loss)
Monotherapy
Dose titration period: 312 weeks
Insulin therapy, MNT, physical
activity, DSME, risk reduction
MNT, physical activity, DSME,
risk factor reduction, SMBG
No more than 12 weeks
Add insulin;
Dose titration period 312 weeks
Adjust management to achieve a
target FPG level of 70 to 110 mg/dl;
Reassess every 3 months
Combination therapy:
Dose titration period 312
weeks
Suggested combinations:
Secretagogues + meformin or
TZD or AGI
Metformin + TZD
Type 1 diabetes
or type 2 with
perisistent severe
symptoms
Asymptomatic
type 2 Diabetes
Yes
Yes
No
No
Key to Abbreviations:
FPG: Fasting Plasma Glucose
TZD: Thiazolidinedione
AGI: Alpha-Glucosidase Inhibitor
DSME: Diabetes Self-
Management Education
MNT: Medical Nutrition Therapy
SMBG: Self-Monitoring of Blood
Glucose
Figure 4. An algorithm of treatment for patients with type 2 diabetes. Reprinted with permission from Ref. 44.
F E A T U R E A R T I C L E
Volume 21, Number 1, 2003CLINICAL DIABETES
20
6
Ohkubo Y, Kishikawa H, Araki E, Miyata T,
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ACKNOWLEDGMENT
The research for this article was sup-
ported by an unrestricted grant from
Aventis.
John R. White, Jr., PA-C, PharmD, is a
professor at Washington State Universi-
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for the Study of Diabetes. Budapest, Hungary,
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913, 2001
Stephen N. Davis, MD, FRCP, is chief
of the Division of Diabetes, Endocrinol-
ogy, and Metabolism at Vanderbilt Uni-
versity Medical School in Nashville,
Tenn. Ramachandiran Cooppan, MD, is
an assistant clinical professor at Har-
vard Medical School in Boston, Mass.
Mayer B. Davidson, MD, is director of
the Clinical Trials Unit at Charles R.
Drew University in Los Angeles, Calif.
Kathryn Mulcahy, RN, MSN, CDE, is
program director of the INOVA Dia-
betes Center in Fairfax, Va. Gary A.
Manko, MD, is president of Clinical
Associates, PA, in Reisterstown, Md.
Donald Nelinson, PhD, is executive
director of the Diabetes Consortium.
The Diabetes Consortium, Inc., is a
nonprofit, multidisciplinary collabora-
tion dedicated to the development and
dissemination of professional and
patient initiatives implementing optimal
diabetes care. For more information,
write to: P.O. Box 8262, Parsippany,
NJ, 07054-8262, or call 877-462-4356.
Note of disclosure: Dr. White has served
on an advisory board for Aventis; has
received honoraria for speaking engage-
ments from Aventis, Takeda, Omron,
Pfizer, and TheraSense; and has received
research support from Aventis. Dr. Coop-
pan has received honoraria from Bristol-
Myers Squibb, Pfizer, Aventis, Novartis,
Takeda, Eli Lilly, GlaxoSmithKline, and
Wyeth-Ayerst. Ms. Mulcahy has served
on advisory boards and received hono-
raria from Aventis and Novo Nordisk. Dr.
Manko has received honoraria from
Pharmacia, Wyeth-Ayerst, and Bristol-
Myers Squibb. All of these companies
manufacture or market insulin or other
pharmaceutical products for the treat-
ment of type 2 diabetes or its complica-
tions.