Group Title: Osteopathic Medicine and Primary Care 2007, 1:9
Title: A practical approach for implementation of a basal-prandial insulin therapy regimen in patients with type 2 diabetes
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Title: A practical approach for implementation of a basal-prandial insulin therapy regimen in patients with type 2 diabetes
Series Title: Osteopathic Medicine and Primary Care 2007, 1:9
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Creator: Edelman S
Dailey G
Flood T
Kuritzky L
Renda S
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Osteopathic Medicine and Primary 0

Care BioMed C



Review

A practical approach for implementation of a basal-prandial insulin
therapy regimen in patients with type 2 diabetes
Steven Edelman*', George Dailey2, Thomas Flood3, Louis Kuritzky4 and
Susan Renda5


Address: 'University of California San Diego, Veterans Affairs Medical Center, San Diego, CA, USA, 2Scripps Clinic, La Jolla, CA, USA, 3Georgia
Center for Diabetes, Atlanta, GA, USA, 4University of Florida College of Medicine, Gainesville, FL, USA and 5Clinical Associates, Reisterstown, MD,
USA
Email: Steven Edelman* svedelman@vapop.ucsd.edu; George Dailey- Dailey.George@scrippshealth.org;
Thomas Flood sugardoctor@mindspring.com; Louis Kuritzky LKuritzky@aol.com; Susan Renda renda4@verizon.net
* Corresponding author


Published: 20 April 2007
Osteopathic Medicine and Primary Care 2007, 1:9 doi: 10.1 186/1750-4732- 1-9


Received: I I December 2006
Accepted: 20 April 2007


This article is available from: http://www.om-pc.com/content/ 1/1/9
2007 Edelman et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.



Abstract
Basal-prandial insulin therapy is a physiologic approach to insulin delivery that utilizes multiple daily
injections to cover both basal (ie, overnight fasting and between-meal) and prandial (ie, glucose
excursions above basal at mealtime) insulin needs. While basal-prandial therapy with multiple daily
injections is an important therapeutic option for patients with type 2 diabetes, there is a common
perception that this therapy is difficult to initiate in the primary care setting. To address this issue,
a panel of clinical experts convened to develop practical recommendations on how to initiate basal-
prandial therapy in patients with type 2 diabetes, focusing on patient selection, simple dosing and
titration, and monitoring. Patients with type 2 diabetes who are appropriate candidates for basal-
prandial insulin therapy include those who: I) are unable to achieve glycemic control on oral
antidiabetic drugs, 2) are unable to achieve glycemic control on split-mixed/premixed insulin
regimens, 3) are newly diagnosed but unlikely to respond to oral antidiabetic drugs alone (ie, the
patient has severe hyperglycemia or a markedly elevated glycosylated hemoglobin Al C level for
which oral antidiabetic drug therapy alone is unlikely to achieve goals), and 4) prefer this therapy
due to socioeconomic or other individual considerations. Basal-prandial insulin can be initiated in
a simple stepwise manner, starting first with the addition of basal insulin to the existing oral
antidiabetic drug regimen, followed by the introduction of I prandial insulin injection to the basal
insulin plus oral antidiabetic drug regimen (after basal insulin has been optimized). Subsequently,
other injections of prandial insulin may be added when needed. Based on home glucose monitoring
data, patients may be converted from split-mixed or premixed insulin regimens to basal-prandial
regimens with similar ease. Basal-prandial therapy using newer insulin formulations, such as long-
and rapid-acting insulin analogs, can be relatively simple to use in patients with type 2 diabetes and
is an appropriate methodology for application by primary care clinicians.


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Osteopathic Medicine and Primary Care 2007, 1:9



Background
Diabetes has reached epidemic proportions in the United
States, with an estimated 20.8 million people (>6% of the
population) affected by the disease and 13 million
patients have been diagnosed [1,2]. An estimated 90%-
95% of cases are type 2 diabetes [2]. Despite abundant
evidence regarding the increased risk of serious micro-
and macrovascular complications associated with poor
glycemic control, only a small proportion of patients with
type 2 diabetes attain the recommended treatment goals
(Table 1). The 2007 American Diabetes Association
(ADA) Clinical Practice Recommendations specify a glyc-
osylated hemoglobin A1C (hereafter A1C) target of <
7.0% for glycemic control [3]. This recommendation is
based on extensive epidemiologic data, [4,5] and recent
clinical studies demonstrate that patients with type 2 dia-
betes can achieve glycemic targets [6]. However, the
National Health and Nutrition Examination Survey
1999-2000 showed that only 37% of adults with diabetes
are achieving the target A1C level of < 7.0% [7]. One
important reason for this is failure to appropriately initi-
ate insulin therapy in a timely manner [8].

The United Kingdom Prospective Diabetes Study demon-
strated the progressive decline in p-cell function that
occurs over time in type 2 diabetes and the eventual need
for insulin therapy in most patients [9,10]. Early introduc-
tion of insulin therapy can attain and maintain glucose
targets when oral antidiabetic drug (OAD) regimens have
failed to achieve glycemic goals, thereby reducing the risk
of diabetes-related complications [11]. Recent consensus
conference recommendations from the American College
of Endocrinology indicate that glycemic targets can be
effectively achieved by basal insulin plus an OAD or basal-
prandial insulin regimens in type 2 diabetes [12].

Basal-prandial insulin therapy with multiple daily injec-
tions is a physiologic approach that attempts to approxi-
mate the normal pattern of pancreatic insulin secretion
[13,14]. Basal insulin suppresses glucose production by
the liver (gluconeogenesis) between meals and overnight
[13,15,16]. Prandial (bolus) insulin covers increases in
blood glucose levels following meals [13]. The combina-
tion of basal and prandial therapy is an important option
for patients with type 2 diabetes when glycemic control is
not achieved with OADs alone or basal insulin plus OAD
therapy [14]. Although primary care clinicians may con-
sider referral of patients considered for basal-prandial
insulin regimens, this strategy can be appropriately imple-
mented within most primary care offices.

Basal-prandial therapy is underutilized in the primary care
setting because it is often perceived as being complex, dif-
ficult to implement, time-consuming, and/or reserved
mainly for patients with type 1 diabetes. However, insulin


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therapy can be implemented in a simple, stepwise man-
ner, by first introducing basal insulin and subsequently
adding prandial insulin (starting with the largest daily
meal and advancing over time to the other 2 meals) as
needed based on pre- and postprandial blood glucose
monitoring. This review provides practical recommenda-
tions for initiating basal and basal-prandial insulin ther-
apy in type 2 diabetes, with a focus on insulin analogs.
The recommendations were developed during a recent
meeting of clinical experts in the field of diabetes. The
meeting was supported by an educational grant from
sanofi-aventis and focused on practical aspects of initiat-
ing insulin therapy including patient selection, dosing,
dose titration, and monitoring (a reference guide on how
to initiate basal-prandial insulin has been developed by
this group and is available as an online resource) [17].

Rationale for Basal-Prandial Insulin Therapy
Both basal and postprandial glucose (PPG) excursions
contribute to hyperglycemia in type 2 diabetes, and treat-
ment strategies that address both components may
enhance attainment of glycemic goals. The ADA guide-
lines call for a fasting plasma glucose (FPG) target of 90-
130 mg/dL and a 2-hour PPG target of< 180 mg/dL (Table
1).

Failure to achieve glycemic control can lead to the devel-
opment of serious diabetes-related complications [4,5].
There is also a growing body of evidence indicating that
postprandial hyperglycemia independently contributes to
an increased risk for macrovascular complications
[4,5,15,16,18-21]. In fact, a meta-analysis of the data has
indicated that isolated postprandial hyperglycemia (2-
hour PPG >140 mg/dL) in the presence of normal FPG (<
110 mg/dL) and normal A1C (< 6.1%) is associated with
a 2-fold increase in the risk of death from cardiovascular
disease [15,21].

A stepwise approach to basal-prandial insulin therapy in
patients with type 2 diabetes allows treatment to be
advanced as the disease progresses to minimize the risk of
complications. Initially, elevated baseline FPG levels lead
to a higher overall plasma glucose profile and conse-
quently higher PPG excursions [16,22]. Also, the relative
contribution of FPG to A1C progressively increases as gly-
cemic control worsens [16,22]. The first goal of a physio-
logic insulin therapy regimen, therefore, is to lower the
overall glycemic profile with basal insulin and normalize,
or nearly normalize, the FPG level [14]. Conceptually, "fix
the fasting first" is the initial agenda. This is accomplished
most efficiently by the addition of basal insulin. Decreases
in PPG excursions may also be achieved by lowering the
overall glycemic profile with basal insulin (Figure 1).
However, as the disease progresses, the capacity of
patients with type 2 diabetes to respond to PPG excur-


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Table I: ADA 2007 Treatment Recommendations [3]


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Glycemic control:


AIC
Preprandial glucose or FPG
Peak postprandial capillary plasma glucose
Keypoints:
* Goals should be individualized
* Special populations may require treatment modifications
* If Al C goals are not met despite reaching preprandial glucose goals,
target treatment to PPG goals if home glucose monitoring data
demonstrate abnormally high blood glucose levels


< 7.0%*t
90-130 mg/dL
< 180 mg/dL


*Referenced to a nondiabetic range of 4.0%-6.0% using a Diabetes Control and Complications
Trial-based assay.
tMore stringent glycemic goals (ie, a normal Al C < 6.0%) may further reduce complications at the cost of increased hypoglycemia risk.
C.:-F.. ,. 2,,,77 American Diabetes Association from Diabetes Care, Vol. 30, 2007; S4-S41 Modified with permission from The American Diabetes
Association


sions becomes progressively impaired due to reduced
endogenous insulin secretion resulting from loss of p-cell
function [9,16]. In many patients, basal insulin alone,
when added to OADs, is sufficient to attain glucose goals.
Due to the natural history of type 2 diabetes, many
patients eventually progress to a level of insulin deficiency
that requires initiation of prandial insulin (or pharmaco-
therapy targeted to prandial insulin control) in addition


to basal insulin. Prandial insulin can be added with the
appropriate meal or meals to control PPG excursions.

Treatment Guidelines
For patients with type 2 diabetes, A1C values ideally
should be measured every 3-6 months. Adjust therapy
when glycemic control is above the ADA target of 7.0%
(Figure 2) [3]. In type 2 diabetes, a progressive decline in
P-cell function should be anticipated and appropriate


Uncontrolled A1C =9.0%


"Controlled" A1C <7.0%


Normal A1C 5.0%-6.0%


0800


1200


1800


0800


Time of Day


Figure I
24-hour glucose profiles for representative patients at different levels of glycemic control. Increasing A IC values
reflect an elevated fasting or preprandial (basal) blood glucose level and elevated PPG excursions. At levels shown as "uncon-
trolled" AIC (9.0%), the culprit is predominantly loss of control of the FPG, whereas the difference between an AI C of upper
normal (6.0%) vs "controlled" AIC (7.0%) predominantly reflects increased PPG. (PG = plasma glucose.) Copyright 2002
From Rationale for and strategies to achieve glycemic control by Cefalu WT. In: Leahy JL, Cefalu WT (eds) Insulin Therapy.
Reproduced by permission of Routledge/Taylor & Francis Group, LLC [41].




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adjustments to therapy made whenever glycemic goals are
not maintained [23].

Practical Recommendations for Patient
Selection
A combination of basal insulin with OADs or basal-pran-
dial insulin therapy are both appropriate treatment
options for patients with type 2 diabetes who are:

* Newly diagnosed and unlikely to achieve glycemic con-
trol with OADs alone (eg, a patient who presents with
markedly elevated A1C [ie, 10.0%]) [24]

* Unable to achieve and/or maintain optimal glycemic
control on diet and exercise plus OADs

* Unable to achieve and maintain glycemic control on
split-mixed or premixed insulin regimens.

Insulin-naive patients who are unable to achieve or main-
tain glycemic goals on OADs can advance therapy to basal
insulin plus OADs then basal-prandial therapy in a step-
wise manner, starting first with the addition of basal insu-
lin to the existing OAD regimen. Prandial insulin is added
to the regimens of patients not achieving glycemic goals
despite well-controlled fasting blood glucose after 3-6
months of basal insulin therapy (Figure 2) [14]. Initially,
prandial insulin therapy may only need to be provided
with the largest meal of the day, or whichever meal pro-
duces the greatest glucose excursions from baseline.

Certain patients with newly diagnosed type 2 diabetes
may benefit from early initiation ofbasal-prandial insulin
therapy, including those with glucose toxicity (ie, pro-
longed hyperglycemia leading to impaired glucose dis-
posal and impaired glucose-stimulated insulin secretion
by p-cells) or latent autoimmune diabetes of adulthood
(LADA). LADA is caused by immune-mediated destruc-
tion of the insulin-producing pancreatic p-cells, similar to
type 1 diabetes but typically is diagnosed in patients aged
30-40 years (the diagnosis is confirmed by blood tests for
the presence of glutamic acid decarboxylase antibodies)
[25,26]. Newly diagnosed patients with A1C >10.0%
require more than a 3.0% reduction in A1C to achieve
ADA target glucose levels [3]. Reductions in A1C of this
magnitude generally will not be achieved with OADs
alone, especially in the face of glucose toxicity, thus such
patients who are symptomatic should be started on basal-
prandial insulin immediately. Once insulin has success-
fully reversed the glucose toxicity, many of these newly
diagnosed patients can then be controlled on OADs
[2,12]. Notably, patients with LADA generally do not
respond significantly to OADs and will require insulin
therapy at an earlier stage than other patients with type 2
diabetes [25-27].


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Finally, patients with type 2 diabetes on split-mixed or
premixed twice-daily insulin regimens who are unable to
achieve or maintain target A1C goals may also benefit
from conversion to basal-prandial insulin regimens [14].
Because the timing of the dose is fixed in such regimens,
they may be ineffective in patients with an unpredictable
daily routine [14]. Patients on these regimens can be
directly converted to a basal-prandial approach using the
protocol described below. In addition, because patient
reluctance to use needles has already been overcome in
this group, it might be easier to transition patients to mul-
tiple daily injections, if necessary.

Preparing the Patient for Basal-Prandial Insulin
Therapy
Clinicians can prepare patients for basal-prandial insulin
therapy by facilitating discussions about insulin and edu-
cating patients on aspects of diabetes self-management,
including the importance of diet and exercise, injection
techniques, carbohydrate counting, home glucose moni-
toring, and hypoglycemia awareness (Table 2). Above all,
it is important that the clinician project a positive attitude
about insulin when discussing this therapy with the
patient [8]. Clinicians should avoid using insulin as a
means for threatening or blaming patients for previous
treatment failure, but rather explain that insulin therapy is
often a natural consequence due to the progressive nature
of the disease: nearly one third of patients with type 2 dia-
betes are likely to require insulin at some point [8]. It is
also important that clinicians discuss and come to an
agreement with patients on specific treatment goals for
basal-prandial insulin therapy [13]. If OADs have failed
due to gross dietary noncompliance, addition of insulin
therapy is unlikely to achieve glycemic goals without ade-
quate diabetes education. Explaining the significance of
A1C measurements, discussing A1C goals, and sharing
results is an important motivational tool for patients on
insulin therapy [8].

Home glucose monitoring is crucial and should be
employed at some level by all patients with type 2 diabe-
tes to provide feedback on both glycemic control and
hypoglycemia [3]. For patients taking multiple insulin
injections the frequency of home glocose montiring
should be at least 3 times daily. While there isn't a specific
guideline for patients on less frequent or no insulin, glu-
cose monitoring is useful in helping achieve glycemic
goals and should be used with increased frequency when-
ever modifications are made to the diabetes regimen.
Patient education on the target range for glucose values,
glucose levels indicating actual or impending hypoglyc-
emia, and appropriate insulin dose adjustment should be
reinforced. Ideally, patients should have access to a certi-
fied diabetes educator, instructional classes, and/or sup-
port groups that can instruct them on home glucose


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Diet + Exercise + 1 OAD (typically metformin)


1 Maximum 3 months


Add Second Agent, Usually Oral (typically a sulfonylurea)

I Maximum 3 months


A1C


A1C >7.0%-8.0%




Consider third OAD
(typically a
thiazolidinedione) or
exenatide or basal
insulin


Maximum 3 m(


A1C 28.0%


months
OADs + Basal Insulin*


A1C >7.0%


3 months
A1C still >7.0%


Add Prandial Insulin as Necessary






*If newly diagnosed with A1C >10.0% and patient is symptomatic, start immediately
with basal plus OADs (typically a sulfonylurea and/or metformin).



Figure 2
Type 2 diabetes treatment algorithm.


monitoring. It is essential that patients understand the
importance of reporting home glucose monitoring results
to the clinician and are encouraged to do so (ie, via email,
fax, phone, in person). This will enhance the clinician's
ability to assess the patient's progress and make timely
dose adjustments. Importantly, patients will be more
informed participants in their own care.

Although severe hypoglycemia is relatively rare in type 2
diabetes, even among patients on insulin therapy, these
events can occur [8]. It is important to educate patients
about symptoms associated with hypoglycemia (Table 3)


and common causes, including failure to eat after taking
insulin, overaggressive use of insulin (ie, increasing the
insulin dose in response to an anomalous blood glucose
concentration), overexercising without adjusting the insu-
lin dose, and alcohol consumption [8,28]. Patients and
family members also need education on how to treat
hypoglycemia (eg, with simple carbohydrates).

Available Insulin and Other Injectable
Preparations
Various insulins with different time-action profiles are
currently available and can be used as part of a basal-pran-


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Table 2: Preparing the Patient for Insulin Therapy


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* Discuss insulin at time of diagnosis of diabetes

* Dispel myths about insulin

* Maintain a positive attitude [8]
Assure the patient that the need for insulin does not represent a personal failure on his or her part
Express confidence in the patient's ability to master self-injection techniques and to maintain appropriate schedules

* Discuss treatment goals with patient [8,43]
Explain the rationale for adding insulin to the treatment regimen and the health benefits associated with improved glycemic control
Allay patient fears about possible negative health consequences associated with insulin therapy
Assure the patient that the need for insulin does not mean his or her diabetes has worsened to a point where it cannot be managed
successfully

* Discuss the patient's day-to-day routine and habits [8]
Identify how food, exercise, and lifestyle choices may influence therapy and treatment goals
Assure the patient that he or she can continue to take part in favorite activities, including eating in restaurants and travel


dial insulin regimen (Table 4). Currently, the intermedi-
ate-acting neutral protamine Hagedom (NPH) insulin
and the long-acting insulin analogs, insulin glargine and
insulin detemir, are available for basal insulin replace-
ment [13,14,29]. Several insulin preparations are now
available for prandial coverage, including the short-acting
regular human insulin, the recently available inhaled
insulin, and the rapid-acting analogs, insulin lispro, insu-
lin aspart, and insulin glulisine [13,14,30].

While use of human NPH insulin has been the mainstay
approach for basal insulin therapy for many years, NPH
often does not adequately and consistently provide 24-
hour basal insulin delivery, necessitating at least twice-
daily dosing in many individuals (Figure 3A) [14,31].
NPH typically has a pronounced peak effect within 4-10
hours of its administration, before returning to baseline
within 10-16 hours [13,14,31]. In contrast, insulin
glargine is a long-acting basal analog that provides insulin
delivery over a 24-hour period without a pronounced


peak (Figure 3B) [13,14,31]. In patients with type 2 diabe-
tes, insulin glargine given once daily has been shown to be
as effective as NPH for improving glycemic control, while
causing significantly less nocturnal hypoglycemia [6]. In a
recent study, the basal analog insulin detemir given twice
daily showed comparable efficacy to NPH insulin with
significantly less nocturnal hypoglycemia [29].

Regular human insulin has traditionally been used to pro-
vide prandial insulin coverage [14]. In comparison to
insulin analogs, this insulin formulation has a delayed
onset of action, requiring it to be administered approxi-
mately 30 minutes before mealtime in order to match its
peak insulin effect to postprandial rises in blood glucose
levels [13,14]. Compared to rapid-acting analogs, regular
human insulin has less dosing flexibility and a longer
duration of action relative to PPG excursions, peaking
within 2-3 hours and returning to basal concentrations
within 3-6 hours (Figure 3A) [13,31]. This prolonged
duration can increase the risk of hypoglycemia if the tim-


Table 3: Symptoms Associated With Hypoglycemia


Hypoglycemia


Nocturnal Hypoglycemia

Nightmares
Night sweats
Tired upon awakening
Irritable upon awakening
Confused upon awakening


Hunger
Excessive perspiration
Confusion
Difficulty speaking
Nervousness
Anxiety
Dizziness
Shakiness
Weakness
Sleepiness
Increased heart rate
Visual disturbances


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Table 4: Time-Action Profiles of Insulins [44]


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Duration of Action (h)


Rapid acting
Lispro, aspart, glulisine
Inhaled insulin [32]
Short acting
Regular human
Intermediate acting
Human NPH
Long acting (basal)
Insulin glargine
Insulin detemir [45]


5-15 min
5-15 min

30-60 min

2-4 h

1-2 h
1-2 h


0.5-1.5
0.5-1.5

2-3

4-10

No pronounced peak
Less pronounced peak (= 6)


Premixed:
Comprised of intermediate-acting insulin with either regular human insulin or a rapid-acting analog in a fixed ratio (eg, 70/30); thus, the onset, peak,
and duration reflect the combined effect of these components.
Copyright 2002 From Insulin therapy in type 2 diabetes mellitus by Ahmann AJ, Riddle MC. In: LeahyJL, Cefalu WT (eds) Insulin Therapy.
Reproduced by permission of Routledge/Taylor & Francis Group, LLC


ing of planned meals is delayed and the patient is on NPH
insulin [13,14]. The newer rapid-acting insulin analogs,
insulin lispro, aspart, and glulisine, are absorbed more
rapidly and are active for a shorter duration than regular
human insulin and thus provide a more physiologic pro-
file (Figure 3B) [30,31]. Rapid-acting insulin analogs have
an onset of action within 15 minutes of administration, a
peak effect within 0.5-1.5 hours, and a return to basal
concentrations within 2-4 hours [13]. Because of their
rapid onset of action, these insulin analogs should be
injected immediately before mealtime [31]. Use of rapid-
acting insulin analogs has been associated with improved
PPG control and a reduced incidence of severe and noctur-
nal hypoglycemia, compared with regular human insulin
[14]. Inhaled insulin, has a more rapid onset and peak of
action, similar to rapid-acting analogs, with a slightly
longer duration of action [32].

Other agents for control of PPG include incretin mimetics
(eg, glucagon-like peptide-1 [GLP-1] analogs) and amylin
analogs. Use of the GLP-1 analog exenatide reduces PPG
and results in weight loss, however, it is not currently
approved for use with insulin [33,34]. The amylin analog
pramlintide is currently approved as adjunctive therapy in
patients using mealtime insulin therapy, and use of this
drug can result in weight loss as well as improved glycemic
control [35].

Dosing and Titration of Basal-Prandial Insulin
Therapy in Insulin-Naive Patients
This section provides practical recommendations for initi-
ating basal and prandial insulin in patients with type 2
diabetes who are not achieving glycemic targets on OADs
alone. Common insulin misuse scenarios are detailed in
Table 5.


Practical Recommendations for Initiation of Basal Insulin
Insulin-naive patients with type 2 diabetes who fail to
achieve or maintain adequate glycemic control on OADs
over 3-6 months should be started on basal insulin ther-
apy. In these patients, a single daily dose of basal insulin
may be added to existing OADs (continued at the same
dosages). Insulin glargine may be safely administered
either at bedtime or in the morning. As long as adminis-
tration is at 24-hour intervals, the time of administration
can be tailored for patient convenience or preference.
NPH and detemir can be given at bedtime (detemir can be
given with the evening meal) but may need to be admin-
istered at least twice daily for basal coverage [36]. Based
on the panel's clinical experience, basal insulin may be
initiated at doses of 10 U in thin patients and 15 U in
obese (body mass index >30 mg/m2) patients. Following
initiation of insulin, patients should monitor FPG levels
using home glucose monitoring. Insulin doses can be
titrated according to self-monitored FPG values using a
titration schedule such as that shown in Table 6[6]. Use of
this algorithm in a clinical trial resulted in an insulin
glargine dose of approximately 0.5 U/kg of body weight
(ie, 50 U in a 100-kg adult). The insulin dose can be
actively titrated until the FPG level is < 100 mg/dL, unless
there are hypoglycemic episodes. Alternatively, insulin
doses may be titrated by the provider or the patient by
increasing the insulin dose 2 U every 3 days until FPG lev-
els are < 100 mg/dL [37]. Recent data suggest that less
aggressive FPG goals may also be effective as long as close
monitoring of glucose and active dose titration of insulin
are implemented [38].

Although NPH may have efficacy in achieving glycemic
control that is comparable to long-acting insulin analogs,
direct comparison trials have shown that rates of overall


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Insulin Type


Onset


Peak (h)


10-16

S24
18-24








Osteopathic Medicine and Primary Care 2007, 1:9


Breakfast Lunch

6 AM 6 10 12-PM 2


Supper Bedtime

6 8 10 12AM 2


NPH NPH
Regular Regular


Breakfast Lunch

6AM h 10 12 M 2


Supper Bedtime

4 6 8 10 12 AM 2


6AM 10

Rapid Rapid
Acting Acting


2 4 8 10 12 AM 2

Rapid Glargine
Acting


Figure 3
Basal-prandial insulin replacement profiles using (A) NPH plus regular human insulin and (B) insulin glargine
plus a rapid-acting insulin. Reprinted with permission from DeWitt DE et al.JAMA 2003, 289:2254-2264 [14].




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4 6 AM


II I I I II I I I I Ij I I I I I I I


4 6AM


4 6 AM


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Osteopathic Medicine and Primary Care 2007, 1:9


Table 5: Practical Recommendations for Optimizing Insulin Use by Primary Care Clinicians


* Avoid delays in the initiation of insulin therapy

* Look for patterns of hyperglycemia when monitoring






and nocturnal hypoglycemia are lower with insulin ana-
logs [6,29]. Bedtime dosing of NPH may predispose
patients to nocturnal hypoglycemia, while morning dos-
ing of NPH may predispose patients to late-morning and
early afternoon hypoglycemia [13].

Practical Recommendations for Initiation of Prandial
Insulin
If AC goals are not achieved after a period of 3-6 months
of treatment with basal insulin plus OADs, patients
should be instructed to monitor glucose preprandially
and/or 1-2 hours after each meal on a rotating basis to
identify the main meal that is contributing to hyperglyc-
emia (ie, high blood glucose levels at breakfast, lunch,
dinner, or bedtime). Once identified, 5-10 U of rapid-act-
ing insulin should be administered before this meal.
Inhaled insulin is currently available as 1-mg and 3-mg
blisters (equivalent to 3 U and 8 U of SC regular human
insulin, respectively). If A1C goals are still not reached
after 3-6 months of therapy with OADs and basal insulin
plus 1 prandial insulin dose at the main meal, prandial
insulin can be added to other meals based on home glu-
cose monitoring. For example, if blood glucose levels are
high before lunch, add 5-10 U of rapid-acting insulin at
breakfast, with continued titration according to the sched-
ule shown in Table 6.

Table 6: Titration Schedule for Basal and Prandial Insulin [6]


* Continue OADs when initiating a basal insulin

* Titrate basal and prandial doses appropriately






Implications of Basal-Prandial Regimens for Existing OADs
The OAD regimen should be continued until the addition
of insulin achieves glycemic control goals. As glycemic
control is established (A1C < 7.0%), OADs can be
adjusted in patients on basal-prandial insulin therapy (eg,
the sulfonylurea dose can be reduced by > 50% as neces-
sary). If subsequent monitoring clearly shows prompt loss
of control, the original dosages of OADs should be
resumed. Once prandial insulin is added to basal insulin
therapy, secretagogues (eg, sulfonylureas) may be discon-
tinued. Metformin therapy should generally be contin-
ued, whereas the decision to continue and/or adjust the
thiazolidinedione dose may be left to physician discre-
tion. Typically, if significant glycemic benefit with the
OAD was achieved prior to starting insulin therapy, the
drug may be continued. In some patients, it may be
appropriate also to reduce basal insulin doses after start-
ing prandial insulin with continued monitoring of FPG
levels.

Practical Recommendations for Converting
Patients from Split-Mixed or Premixed Insulin to
Basal-Prandial Insulin
If split-mixed or premixed insulin regimens fail to achieve
or maintain adequate glycemic control, these may be con-
verted to basal-prandial insulin therapy as follows: the


Blood Glucose Levels for 3 Consecutive Days
(Fasting, Preprandial, or Bedtime)


Adjust Basal Insulin Dose (U)*


Adjust Rapid-Acting Insulin Dose (U per Injection)


Maintain dose
-2


Maintain dose
-2
-2


* For elevated fasting blood glucose For elevated preprandial blood glucose at lunchtime,
levels, adjust only the basal insulin dose adjust breakfast rapid-acting insulin dose
For elevated preprandial blood glucose at dinnertime,
adjust lunchtime rapid-acting insulin dose
For elevated bedtime blood glucose, adjust
dinnertime rapid-acting insulin dose


*C:op.F. ~;h 2,'"'3 American Diabetes Association from Diabetes Care, Vol. 26, 2003; 3080-3086. Modified with permission from The American
Diabetes Association.
tlf any single blood glucose measurement is in this range, make the appropriate reduction in insulin dose.


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>180 mg/dL
160-180 mg/dL
140-160 mg/dL
120-140 mg/dL
100-120 mg/dL
80-100 mg/dL
60-80 mg/dLt
< 60 mg/dLt
Comments:


hftp://www.om-pc.com/content/l/l/9







Osteopathic Medicine and Primary Care 2007, 1:9



total daily dose of NPH insulin (intermediate-acting insu-
lin) should be reduced by 20% in order to calculate the
initial dose of the long-acting insulin analog as shown
below:

Calculating the initial basal insulin analog dose

1. Determine the total daily dose of NPH

2. Decrease dose of NPH insulin by 20%

Example: A patient on 50 U premixed 70/30 (NPH 35 U; reg-
ular human insulin 15 U) twice daily

1. Total daily dose of NPH = 70 U

2. Long-acting analog dose = 80% of 70 U NPH = 56 U

Insulin glargine can be administered once daily either at
bedtime or in the morning. Insulin detemir can be admin-
istered once daily with the evening meal or at bedtime or
twice daily with a morning dose and an evening dose 12
hours later. Following initiation of a basal insulin analog,
patients should be instructed to monitor FPG and adjust
their dose according to the suggested titration algorithms
(Table 6).

A rapid-acting insulin may need to be added to 1 or more
meals (eg, at lunchtime since the morning NPH insulin
has been eliminated-this can be determined by monitor-
ing postlunch or predinner glucose levels). The dose of
rapid-acting insulin can be directly calculated from the
dose of regular human insulin:

Calculating the initial rapid-acting insulin dose:

1. Determine the total daily dose of regular human insulin

2. Rapid-acting dose per meal = total daily dose of regular
human insulin + 3

Example: A patient on 50 U premixed 70/30 (NPH 35 U; reg-
ular human insulin 15 U twice daily)

1. Total daily dose of regular insulin = 15 U twice daily =
30 U

2. Rapid-acting dose per meal = 30 U + 3 = 10 U

NOTE: Pre- and/or postmeal blood glucose should be
monitored to assess the need for further dose adjustment.

As is the case with basal insulin, the dose of rapid-acting
insulin should be titrated according to the titration sched-
ule shown in Table 6.


http://www.om-pc.com/content/1/1/9


Converting patients to a basal-prandial insulin regimen
using a morning dose of a basal insulin analog
The recommended strategy for converting patients to a
basal-prandial regimen using morning doses of a basal
insulin analog differs slightly from those for patients
using bedtime doses. Patients should be given, on the
prior evening, a predinner dose of split-mixed insulin
(NPH plus regular human insulin) or a predinner dose of
premixed insulin as usual. Then they can be administered
an initial dose of the basal insulin analog the following
morning, with a rapid-acting insulin provided at meal-
time(s) as needed.

Converting patients to a basal-prandial insulin regimen
using a bedtime dose of a basal insulin analog
Patients starting basal-prandial insulin therapy with a
long-acting analog administered at bedtime should take
their morning dose of split-mixed insulin (NPH plus reg-
ular human insulin) as usual (they may also take the usual
dose of regular human insulin at dinnertime but not a
predinner dose of NPH). Patients should then administer
the basal analog at bedtime. Starting the following morn-
ing, a rapid-acting insulin may be provided at meal-
time(s) as needed.

Practical recommendations for home glucose
monitoring
Home glucose monitoring ideally should be performed
3-4 times per day at least initially [3,13]. However,
because insurance companies often do not pay for more
than 2-3 test strips per day, the following recommenda-
tions have been developed as a best practice minimum.

Premeal glucose levels should be tested twice daily before
meals and at bedtime. For example, on odd-numbered
days of the month, premeal glucose levels should be
tested before breakfast and lunch. On even-numbered
days of the month, premeal glucose levels should be
tested before dinner and at bedtime. Recommended
blood glucose targets are 90-130 mg/dL before meals [3]
and 100-140 mg/dL at bedtime.

Patients with premeal glucose levels outside the 90-130
mg/dL range may have dietary factors that are impacting
their glucose levels or simply require more insulin.
Patients should be instructed to take a dietary history to
collect additional information on their eating habits and
how these habits may be affecting blood glucose levels (ie,
snacking between meals). Blood glucose levels may need
to be monitored more frequently in these patients over a
short period of time, ideally 4 times per day for at least 2
weeks.

Patients with premeal glucose levels within the recom-
mended target range, but who remain above A1C goals,


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Osteopathic Medicine and Primary Care 2007, 1:9




will require even more specific guidance on how to refine
glucose control. Hence, to define whether PPG immedi-
ately postmeal is the culprit responsible for inadequate
control, they should be instructed to specifically monitor
2-hour PPG levels [39]. Another useful monitoring strat-
egy is to have patients "frame" a meal by checking pre-
meal and 2-hour PPG. Patients can choose a different
meal each day. Monitoring both premeal and 2-hour PPG
may help identify problem meals undetected by premeal
glucose monitoring alone. A dietary history should also
be taken for these patients. Continuous glucose monitor-
ing is now available and is an important advancement in
the management of diabetes since patients will have
improved their ability to adjust insulin and to better antic-
ipate and therefore prevent hypoglycemia [40].

Conclusion
Basal-prandial insulin therapy provides a physiologic
approach to the treatment of patients with type 2 diabetes.
It can be an appropriate treatment option for a range of
patients, including those who are unable to achieve glyc-
emic control on OADs, certain patients with newly diag-
nosed diabetes and glucose toxicity who are unlikely to
adequately attain goals by means of OADs, and patients
who are unable to achieve glycemic control on split-
mixed or premixed insulin regimens. The availability of
newer rapid-acting and long-acting insulin analogs that
closely mimic normal endogenous prandial and basal
insulin secretion provides an unprecedented opportunity
for more physiologic insulin replacement. The proposed
approach for dosing, titration, and monitoring of basal-
prandial insulin therapy can assist primary care clinicians
in initiating and converting patients to basal-prandial
insulin regimens consisting of basal insulin and rapid-act-
ing insulin in a straightforward and stepwise manner.

Competing interests
Steven Edelman, MD, George Dailey, MD, Thomas Flood,
MD, and Susan Renda, CRNP, CDE, declare they have no
competing interests.

Louis Kuritzky, MD, is or has been on the speakers bureau
for Eli Lilly and Company, sanofi-aventis US, and Pfizer
Inc.

The expert panel meeting which provided the basis for the
recommendations in this article was supported by an edu-
cational grant from sanofi-aventis.

Authors' contributions
Each author was involved in the discussion of the concept
of this article, revising it critically for important intellec-
tual content and provided final approval of the manu-
script.


http://www.om-pc.com/content/1/1/9


Acknowledgements
The author gratefully acknowledges Katie Singh, PharmD, of Embryon who
assisted in the preparation of a first draft of this article based on an author-
approved outline and assisted in implementing author revisions. Embryon
supports the Good Publications Practice Working Group guidelines on the
role of medical writers in developing scientific publications http://www.gpp-
guidelines.org. This article was supported by sanofi-aventis US.

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