Chaque forme pharmaceutique présente ses propres avantages et inconvénients antibiotiques en ligne
mais n'ont pas d'effets néfastes pour l'organisme dans son ensemble.
July 2003 Body.qxd 7/14/03 8:52 AM Page 189
Clinical Medicine & Research
Volume 1, Number 3: 189-200
2003 Clinical Medicine & Research
Current Therapeutic Options in Type 2 Diabetes Mellitus:
A Practical Approach
Michael T. Sheehan, MD, Department of Endocrinology, Marshfield Clinic-Wausau Center, Wausau, Wisconsin
[See related article 173 - 174]
The incidence of type 2 diabetes mellitus (DM) in the United States continues to grow rapidly, paralleling the overweight and obesity
epidemic. For many years the only therapeutic options for type 2 DM were sulfonylureas and insulin. However, over the last 9
years there has been an explosion of new and exciting agents approved for the treatment of type 2 DM. Some of the treatments
target insulin deficiency and others insulin resistance, the hallmarks of the disease. Other drugs delay the intestinal absorption of
carbohydrate. Recently several combination agents have been released. With these new drugs has come an overwhelming
mountain of information, making it difficult for the busy clinician to know how best to manage the ever-increasing portion of
patients with type 2 DM.
New questions have arisen: Which agent to start as first line? How much of this drug to use before adding something else? Howlong for this drug to reach full effect? Which agent to add second? Should a patient uncontrolled on dual therapy begin insulin orstart a third oral agent? If insulin therapy is started, what should become of the patient's oral agents? How best to explain thepatient's weight gain on therapy? These are not easy questions and no review can fully detail all the therapeutic combinations possible. Instead, the practical approach of reviewing the agents in terms of their mechanism of action and critically comparingtheir dosing, effect and cost, is undertaken herein. Also addressed is the possible niche some newer classes of agents and combination drugs may or may not hold in the management of type 2 DM. The decision of using insulin versus a third oral agentwill be looked at from the standpoint of where the patient is on dual therapy in relation to the hemoglobin A1c goal. In this way it is hoped that some clarity will be brought to the dizzying array of information that both the physician and patient have to deal within regard to the management of this prevalent and serious disease.
MARCH 31, 2003
REVISED AND ACCEPTED: JUNE 11, 2003
Michael T. Sheehan, MD
Type 2 DM; Insulin secretagogues; Insulin sensitizers;
Department of Endocrinology
Diabetes therapy; Glucose absorption inhibitors
Marshfield Clinic-Wausau Center2727 Plaza DriveWausau, WI 54401
Dr. Sheehan serves on the Speaker Bureaus for the
following pharmaceutical companies: Takeda,
GlaxoSmithKline, Lilly, Aventis and Pfizer.
July 2003 Body.qxd 7/14/03 8:52 AM Page 190
tinue as even newer agents with completely different mecha-nisms of action are currently under investigation. Along with
Vast amounts of literature have been written about the cur-
this explosion of therapeutic options has come uncertainty
rent and growing epidemic of diabetes mellitus (DM) and its
over how to use these agents effectively. When thought of
associated complications. The cost of diabetes to the United
simply, there are but three ways in which these agents work
States healthcare system is staggering, amounting to $100
toward improving glycemic control: (1) increasing insulin
billion in direct and indirect expenditures annually.1 Currently
secretion [insulin secretagogues], (2) increasing insulin
15 million Americans have diabetes, one third of whom have
action [insulin sensitizers], and (3) decreasing insulin need
yet to be diagnosed. Ninety percent of these cases represent
[inhibitors of glucose absorption].
type 2 DM. The incidence of type 2 DM and its precursor(impaired glucose tolerance) continues to rise, paralleling that
Increasing insulin secretion (secretagogues)
of overweight and obesity.2 Frighteningly, this is occurring
in children and adolescents, as well as adults.3 Over the last
These agents were first introduced for the management of
9 years a growing number of oral medications and newer
type 2 DM in the mid-1950s. These were the only oral agents
insulin analogs have become available for use in type 2 DM.
available in the United States until 1994. These drugs work
The optimal use of these agents has become more difficult
by binding to a regulatory protein (commonly referred to as
with the increased complexity a greater number of choices
the SU receptor) on pancreatic β-cells, which in turn, results
bring. This task is made more challenging with the pharma-
in closure of ATP-dependent potassium (K
ceutical industry spending large sums of money annually in
leading to membrane depolarization and influx of calcium
direct marketing toward physicians and patients.4 For better
through voltage-dependent channels, which subsequently
or worse, prescribing patterns are affected by this marketing,
leads to insulin secretion.7
or obviously such amounts of money would not be so spent.5
It should be stressed that despite the vast literature available,
As the second generation SUs are currently the most widely
many patients and physicians alike still view type 2 DM as a
used, this discussion will be limited to these agents. The
"less severe" illness than type 1 DM. On the contrary, because
dosing, and the cost and effect of the SUs on HbA1c are
of the much greater prevalence of type 2 DM, the great
summarized in table 1. As is apparent, their relative potency
majority of microvascular complications occurs in these
is similar. The most common side effect of the SUs is hypo-
patients. The increased risk of cardiovascular disease (CVD)
glycemia, the risk of which varies somewhat among the
in type 2 DM has led to more stringent goals for the
agents. It is generally accepted that glyburide has twice the
management of cholesterol and blood pressure, in addition
risk of hypoglycemia compared to the other second generation
to the use of aspirin.6 Therefore, close attention should be
SUs.8,9 This is due to increased duration of binding to the
paid to the overall cardiovascular health of patients with
SU receptor, resulting in fasting hyperinsulinemia with gly-
type 2 DM, not just their hemoglobin A
buride. This degree of fasting hyperinsulinemia is generally
not seen with the other SUs, which are more glucose-sensi-
The optimal management of type 2 DM cannot be discussed
tive (and thus prandial) in their stimulation of insulin secre-
by simply outlining what agents are available along with
tion.9 An additional factor in this regard is glyburide's
their doses, effectiveness and side effects. More difficult
suppression of several counter-regulatory hormones. Weight
management issues need to be explored as well. Also, as
gain is variable, but tends to be greatest with glyburide, which
CVD is so prevalent in patients with type 2 DM the
relates to its greater propensity to induce hypoglycemia. There
potential for non-glycemic benefits of some of the newer
is some evidence that glipizide-gastrointestinal therapeutic
agents deserves mention. This review will focus not only on
system (glipizide-GITS) and glimepiride are more weight
the oral agents per se, but also on their proper use over time
neutral.10 Also, the potential for decreasing myocardial
and in combination. The potential benefit of non-glycemic
protective mechanisms via cross-reactivity of SUs with
effects of some agents will be mentioned briefly. The use of
myocardial KATP channels seems to be greater with glyburide
insulin in combination with oral agents will also be described.
than other SUs.11
It is hoped that through a better understanding of these agentsproviders of care for patients with type 2 DM will be aided
The clinical importance of this is not known, but the contro-
in the most difficult task of preventing the complications of
versy regarding increased risk of myocardial events with
SUs noted in the University Group Diabetes Program12,13has finally been put to rest by the United Kingdom Prospective
ORAL AGENTS AVAILABLE FOR THE
Diabetes Study (UKPDS) where a decreased
event rate fell
TREATMENT OF TYPE 2 DM
just short of statistical significance.14 Another concern laidto rest by the UKPDS it that SUs may hasten the demise of
Prior to 1994 selecting an oral agent for the treatment of
the β-cell. On the contrary, by the end of the study those on
type 2 DM was as simple as choosing which sulfonylurea
SU therapy had higher β-cell function than those not on
(SU) to use. Since then, a variety of newer agents with
such therapy because of increased insulin secretion in the
unique mechanisms of action and even some combination
first year, the rate of decline thereafter paralleling that of the
agents have been released for use as monotherapy or in any
other groups (figure 1).15 These agents and their metabolites
number of combination regimens. This trend is likely to con-
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July 2003 Body.qxd 7/14/03 8:52 AM Page 191
Dosing, efficacy and cost of oral agents for treatment naïve type 2 diabetes mellitus patients.
1.25/250, 2.5/500, 5/500
1/500, 2/500, 4/500
2.5/250, 2.5/500, 5/500
a Approximate hemoglobin A (HbA ) reduction versus placebo at maximally effective dose, except where indicated.
b Cost of maximally effective dose, average wholesale price for brand name, or maximal allowable cost as set by a regional insurer for generic.
c Generic preparations. d 10 mg bid dosing.
e 10 mg qd dosing.
f 8 mg tablets, 1/2 bid (4 mg bid: $1,975/year).
g Represents equivalent maximally effective doses of components.
h Mean dose 4.1 mg/824 mg daily (Glucovance package insert).
i No clinical efficacy trials conducted.
j Mean dose 7.4 mg/1477 mg daily (Metaglip package insert).
Glucophage-XR, Glucovance and Metaglip (Bristol-Myers Squibb Company, Princeton, NJ).
* Avandamet (GlaxoSmithKline, Research Triangle Park, NC).
* Glipizide gastrointestinal therapeutic system (glipizide-GITS).
are excreted by various degrees via the kidneys. Caution
In terms of overall potency, repaglinide is equivalent to the
should be used in the setting of renal insufficiency. Of the
SUs, with nateglinide being less effective (table 1). As
second-generation agents, glyburide may be of most concern
they are metabolized and excreted by hepatic mechanisms
in this regard with the others being generally safer in mild
exclusively, these agents can be safely used in more
renal insufficiency.16 Overall, the SUs are a potent, safe and
advanced renal insufficiency (vs. glimepiride for example).
cost-effective management option in type 2 DM.
Much has been said in regard to the ability of these agents to
control postprandial glucose (PPG) because of their faster
Repaglinide and nateglinide were released in 1998 and 2001,
onset of action. There is no doubt that control of PPG is
respectively. These agents are not SUs. These agents are also
important in the optimal control of type 2 DM. There is also
a different class from each other, repaglinide being a mem-
evidence that increased PPG levels may translate into a
ber of the meglitinide family and nateglinide a derivative of
greater risk of CVD.18 If PPG levels are targeted, the goal
phenylalanine. The main difference between these agents
should be <140 mg/dL at 2 hours, as documented by the
and the SUs is the rapidity and duration of stimulation of
American Diabetes Association position statement.19 The
insulin secretion. The non-SUs differ from SUs in two
unanswered question is how best to achieve this postprandial
ways:17 (1) dosing at each meal, (2) potentially less risk of
hypoglycemia, especially if a meal is missed.
Therapeutic options in type 2 DM
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Despite the methods in which these newer insulin secreta-
Increasing insulin action (insulin sensitizers)
gogues have been marketed, there is little published evidence
they control PPG better than the SUs. Indeed, Landgraf et al.
Metformin had been in widespread use overseas for many
failed to show a significant difference in PPG between
years before being approved in the United States in 1994.
repaglinide and glibenclamide (glyburide).20 However,
This delay was due to the high risk of fatal lactic acidosis
nateglinide did fare somewhat better than glyburide, with a
with phenformin, which was removed from the United States
PPG of <140 mg/dL achieved in 30% and 13%, respectively.21
market in the mid-1970s. The risk of this severe complica-
Recently, data has emerged comparing glipizide to both
tion is 10 to 20 times lower with metformin, and is limited
repaglinide22 and nateglinide23 revealing little, if any,
to those with renal insufficiency and other predispositions to
difference in PPG control (figure 2). In fact, the conclusion
acidosis, such as chronic pulmonary disease and congestive
of Carroll et al. went as far as to say,
heart failure.24 Metformin's actual mechanism of action isnot fully known, but its main effect is to decrease hepatic
"The clinical decision to use glipizide versus nateglinide
gluconeogenesis, thus improving fasting hyperglycemia.25
should be based on factors other than the control of post-
There is also a peripheral effect of improved insulin action
prandial hyperglycemia in type 2 diabetes."23 Although not
in muscle tissue, which may be related to metformin's ability
directly compared with the non-SU secretagogues, glimepiride
to lower free fatty acids (FFA)26,27 and/or its induction of
also has a significant effect on PPG control.11 The usefulness
mild weight loss through decreased caloric intake.
of these agents remains to be seen and must take intoaccount their increased cost, and what differences there truly
Metformin is likely the initial treatment of choice for most
are versus the SUs in terms of PPG control.
patients with type 2 DM for a variety of reasons. By improving insulin sensitivity it also improves a variety ofother factors related to increased cardiovascular risk.28 Theseimprovements in surrogate markers do indeed translate intodecreased event rates. Although the exact mechanism wasunclear in the obese cohort of the UKPDS, metformin (vs.
conventional therapy) was shown to significantly reduce therate of myocardial infarction and all-cause mortality.29Metformin is also advantageous in that it is often weightneutral or induces slight weight loss through its appetite-suppressive action. This is true of monotherapy and in combination with other agents.
The main side effect of metformin is gastrointestinal intolerance (nausea, abdominal pain and diarrhea), whichoccurs in approximately 30% of patients.30 This problem isrelated to total dose and the rapidity with which the
. β-cell function in patients allocated to diet therapy
(❍), sulfonylurea (▲), or metformin (■)
medication is titrated upward. Much of this difficulty can be
(adapted from reference 15).
avoided by administration with food and by increasing thedose by 500 mg per day, every 1 to 2 weeks (thus allowing 3 to 7 weeks before a full dose is reached). Very fewpatients need to discontinue metformin due to adverseevents when these guidelines are followed. As mentioned,the risk of lactic acidosis with metformin is minimal so longas its use is avoided in those at risk (serum creatinine ≥1.5mg/dL in men or ≥1.4 mg/dL in women). When uncertaintyarises as to the validity of serum creatinine, creatinine clearance should be measured or calculated (≥60 mL/minuteis considered safe). Metformin should also be avoided inpatients with liver disease or habits that put them at risk ofsuch (alcohol abuse and/or binge drinking) and other conditions that may predispose to acidosis (congestive heartfailure and/or pulmonary disease). Its use in patients over 80 years of age also carries greater risk. Lastly, metforminshould be held for 48 hours prior to and after surgery and/or
Mean postprandial plasma glucose excursions
administration of radiocontrast materials.
from baseline with glipizide () or nateglinide (❍) after astandardized breakfast in 20 subjects with type 2 diabetes(adapted from reference 23). G, glipizide; M, meal; N, nateglinide.
CM&R 2003 : 1 (July)
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It deserves mention that an extended-release metformin,
responders are looked at separately, the potency is comparable
Glucophage XR (Bristol-Myers Squibb Company, Princeton,
to other agents (see later).44 Their effect on glucose control
NJ), is now available allowing once daily administration.
may be more sustained over time than that of other
Although priced less than brand name Glucophage (Bristol-
agents.37,38 The durability of glucose control over time with
Myers Squibb Company, Princeton, NJ), it is significantly
glyburide, metformin, or rosiglitazone in newly diagnosed
more expensive than generic metformin (table 1). While
type 2 diabetics will be definitively addressed in A Diabetes
studies showed only a 9.5% incidence of diarrhea, it should
Outcome Progression Trial (ADOPT).45
be recognized that this low rate might have stemmed fromthe much lower incidence of diarrhea in the entire study. In
Like metformin, the TZDs have widespread beneficial
fact, the risk of diarrhea with Glucophage XR was 3 to 4.5
effects on a variety of surrogate markers of cardiovascular
times that of placebo, a similar degree of increase over
risk; extensive study is ongoing in this area. Perhaps the
placebo seen in trials of metformin (Glucophage XR package
most noticeable of these non-glycemic effects is the ability
insert). Also, in these same trials there was an unexplained
of the TZDs to raise high-density lipoprotein (HDL)
increase in triglyceride levels with Glucophage XR that was
cholesterol by up to 13%.32,39-43,46 Furthermore, there may
not seen in trials of metformin. Thus, there seems to be no
be a differential effect on HDL subtypes with rosiglitazone,
benefit of Glucophage XR beyond that of once daily dosing,
preferentially effecting HDL-2 (the most protective HDL
which is unlikely to be worth the increased cost versus
subfraction).46 The effects on triglycerides and low-density
lipoprotein (LDL) levels tend to be more variable and thereis mounting evidence that pioglitazone performs consistently
better in these regards than rosiglitazone.39-43 A double-
With the introduction of troglitazone in 1997, an exciting
blind, placebo-controlled, parallel design, phase IV study
new era in the management of type 2 DM dawned. Despite
directly comparing the effects of these two agents on the
the removal of troglitazone from the market in 2000 because
lipoprotein profile is currently underway. Despite their
of liver toxicity, two newer agents, rosiglitazone and
tendency to increase total LDL cholesterol, the TZDs shift
pioglitazone (approved in 1999), continue in widespread use
the LDL particle size to larger, less atherogenic molecules,
without evidence of similar problems.31 However, the edema
although it is uncertain what this means to overall cardio-
and weight gain seen with the TZDs can be limiting in some
patients. These agents bind to peroxisome proliferator activator receptor-gamma nuclear receptors affecting gene
In addition to these effects on lipid parameters, the TZDs
regulation in target cells. Interestingly, this alteration of gene
beneficially affect plasminogen activator inhibitor, C-reactive
transcription takes place in adipocytes and the genes concerned
protein, endothelial function, smooth muscle proliferation
primarily regulate fatty acid metabolism, the net result of
and carotid intimal media thickness. Extensive reviews on
which is to decrease serum FFA by approximately 20% to
this subject can be found.47,48 Despite this growing body of
40%.32-34 This reduction in FFA, in turn, improves insulin
circumstantial evidence, the most crucial question remains
action in muscle tissue, thus implicating elevated FFA as a
unanswered; will the use of TZDs translate into a reduction
major contributor to insulin resistance. Further-more, this
in cardiovascular events? The answer will be known the
reduction in FFA improves β-cell function by decreasing
latter part of this decade. The following trials will definitely
lipotoxicity, a process whereby increased FFA eventually
settle these issues:
leads to β-cell death.35 In various trials the TZDs have
- Rosiglitazone Evaluated for Cardiac Outcomes and
increased β-cell function by up to 60%.33,35,36 Unlike the
Regulation of glycemia in Diabetes (RECORD);
increase in β-cell function seen with SUs in the first year of
- Action to Control CardiOvascular Risk in Diabetes
the UKPDS, the increased functional capacity induced by
TZDs is maintained for at least 2 years.37,38
- Bypass Angioplasty Revasculization Investigation Type 2
Both agents have been approved for use as monotherapy
- PROspective Actos Clinical Trial In macroVascular Events
and in combination with other oral agents. They are not
(PROactive [Actos, Takeda Pharmaceuticals North
approved for use in most triple therapy regimens, except for
America, Inc., Lincolnshire, IL]).
the combination of Glucovance (Bristol-Myers Squibb Company, Princeton, NJ) and rosiglitazone. Pioglitazone
These issues of durable control over time and cardiovascular
and rosiglitazone have been approved in combination with
outcomes are of great importance not only to physicians
insulin. TZDs are contraindicated in patients with liver
caring for patients, but also to help healthcare systems determine
disease and those with New York Heart Association class III
whether these slightly less potent agents are worth their cost.
or IV cardiac status. From a therapeutic standpoint, there islikely no significant difference between these agents in
Decreasing insulin need (inhibitors of glucose absorption)
terms of glucose-lowering effect39-43 and they may be
ALPHA-GLUCOSIDASE INHIBITORS (AGIs)
slightly less potent than the SUs or biguanides (table 1).
The two agents in this class currently available, acarbose and
This apparent decreased potency may be related to a
miglitol, were released in 1996. These drugs only affect PPG
significant rate of non-responders; however, as when
levels and do so by competitively inhibiting the binding of
Therapeutic options in type 2 DM
CM&R 2003 : 1 (July)
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oligosaccharides to the alpha-glucosidase enzyme in the
Several points regarding the insulin sensitizers warrant
brush border of the small intestine. This enzyme cleaves
mention here as well. First, metformin dosages beyond
oligosaccharides to monosaccharides, which can then be
1,000 mg twice daily will unlikely offer further benefit and
absorbed. Thus, when taken with the first bite of food, these
may increase the risk of gastrointestinal side effects that
agents delay the absorption of carbohydrate. These drugs do
could potentially result in the discontinuation of this extremely
not cause hypoglycemia or weight gain. However, because
useful agent.30 The effect of metformin on glucose control is
they only affect PPG levels the potency of the AGIs is
also seen fairly quickly, on the order of one to two weeks.
significantly less than most other agents (table 1). For this
The TZDs are somewhat less confusing in this regard in that
reason and for the often significantly troublesome side
the maximal prescribable dose is the same as the maximally
effects of flatulence, abdominal pain and diarrhea, these
effective dose. However, with rosiglitazone it should be
agents are used sparingly in the United States.
noted that 4 mg twice daily may be more potent than 8 mgonce daily.32 Lastly, it should be realized that it takes more
IMPORTANT MANAGEMENT ISSUES IN
time for the TZDs to demonstrate full effect than the other
oral agents (3 to 4 months vs. several weeks).32,33,36
Maximal prescribable dose vs. maximally effective dose
As mentioned previously, the cost of diabetes on the United
States healthcare system is staggering. As newer, more
Within the last 2 years several combination agents have been
costly treatment modalities become available, physicians
released for use in the management of type 2 DM. The
need to be increasingly aware not only of the agents
patient-friendly nature of these agents is a frequently sited
themselves, but also of how to use them cost-effectively.
benefit. "By prescribing these agents physicians can
The maximal prescribable doses and maximally effective
decrease cost (one co-pay) and increase compliance (fewer
doses are listed in table 1. There is some debate as to the
tablets)." The issue of cost certainly is important. However,
validity of describing a "maximally effective" dose because
the number of co-pays is but one factor in medication
of the high degree of variability in response to SUs.49-51
expenditures. Increased use of more expensive combination
While the author uses the listed maximally effective doses as
agents could increase overall drug cost indirectly by
such for glyburide and glimepiride, clinical experience has
increasing insurance premiums. In regard to compliance,
led to utilizing up to 10 mg bid for glipizide and 10 mg qd
there is published evidence–and it makes intuitive sense–that
compliance is higher with one drug versus two.55 Compliancehowever, is more complex than pill number or frequency,
Significant cost savings can be achieved by a better under-
and in the author's opinion, is more strongly affected by
standing of the maximally effective dosage of medications
physician-patient discussions that occur (or do not occur)
and how quickly to expect to reach that full effect. Savings
in regard to combination therapy. An informed patient is
can then be achieved on several fronts:
more likely to comply with therapy than an uninformed or
- Avoidance of prolonged therapy that is unlikely to work.
- Use of only as much of a given agent as is needed.
For a combination agent to be useful it should be comparable,
- More timely addition of other treatment modalities.
if not less, in cost to its components and should involve
An all too common scenario is when an uncontrolled patient,
fewer tablets daily (and/or decreased frequency of dosing).
for example with a HbA1c of 10.5% on glyburide 10 mg
With this in mind, it is interesting to see that the various
daily, is told to increase to 10 mg twice daily and follow-up
combination agents available do not fare well (table 2).
in several months. A more appropriate sequence of events
Indeed, none offer fewer tablets daily than the components
might start with the realization that the effect of glyburide is
taken separately. In reference to cost, only Avandamet
close to full at 10 mg daily and any increase will certainly
(GlaxoSmithKline, Research Triangle Park, NC) offers
not get this patient to goal. Secondly, even if a dose increase
savings over its components separately (approximately $400
was attempted, the full effect of an SU would be seen within
per year less). There is some unpublished, retrospective data
1 to 2 weeks, with follow-up planned accordingly.52 Delayed
suggesting that Glucovance lowers HbA1c to a greater degree
follow-up only allows for continued poor control of diabetes,
than similar doses of metformin and glyburide separately.
further raising the risk of costly complications. How many
These results suggest a benefit of 0.13% to 0.6% with
patients are being treated with an SU dose beyond what
Glucovance. Until these results can be confirmed by a
they need and at what extra cost? Generally, increasing an
prospective, randomized trial, they should be interpreted
SU from the maximally effective to maximum dose leads to
with caution. Even if confirmed, the cost-effectiveness of
an additional HbA1c lowering effect of ≤0.4% while
this benefit (an additional $700 annually) is unclear.
doubling cost.49,50,53,54 Granted these medications areamong the least expensive, but they are also the most widely
Dual therapy options
prescribed. Thus, the savings of optimal dosing would likely
As was shown in the UKPDS, most patients with type 2 DM
will eventually require multiple oral agents to maintain optimal glycemic control. With the availability of newer
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July 2003 Body.qxd 7/14/03 8:53 AM Page 195
agents that target not only the defect in insulin secretion, but
First, how far from goal is the patient? This is important in
also insulin action, a variety of combination strategies are
terms of both whether to add a TZD or start insulin, also
now possible. A full discussion of these options is beyond
how intense an insulin program to start, if need be. The
the scope of this review, but several excellent summaries are
addition of a TZD as a third agent is beneficial in about
available.56,57 In general, the combination of an insulin
60% of patients.44 In those who respond the effect can be
secretagogue and sensitizer is most often used and makes
substantial with a mean HbA1c reduction of approximately
intuitive sense given the two major pathogenic mechanisms
2.5% seen in a troglitazone trial.44 When taken as a whole
of type 2 DM (insulin resistance and insulin deficiency).
(responders and non-responders alike), the mean reduction
Most often this involves the use of metformin and an SU, as
in HbA1c by adding troglitazone third line was only 1.4%.58
this combination brings together high potency, low cost and
In the only published trial (in letter form) of the currently
a low potential for weight gain. Certainly, a TZD should be
available TZDs, rosiglitazone added to glimepiride and met-
substituted for metformin in the case of contraindications to
formin therapy,59 led to a 1.4% reduction in HbA1c. Patients
the latter. The use of non-SU secretagogues and/or AGIs
whose HbA1c is above 9.5% on dual therapy are unlikely to
brings increased cost, decreased potency, and more potential
get to goal by the addition of a TZD. A trial can be given to
for side effects (with AGIs).
these patients (especially those particularly averse to insulintherapy), but follow-up for consideration of other options
The potential utility of metformin plus a TZD as dual therapy
should be scheduled after 3 months at maximal dose. The
is interesting. From the standpoint of annual cost, this com-
TZD should be discontinued if the patient does not respond.
bination ($2,500) is certainly more expensive than metformin
If the decision to start insulin is made it should be stressed
plus SU ( $800). Metformin plus TZD is also slightly less
that adding bedtime insulin to daytime oral agent therapy
potent than metformin or TZD plus SU.56,57 However,
will only lower HbA1c by 2% to 2.5%.60 Therefore, if the
despite both being insulin sensitizers, this combination still
HbA1c is above 9.5% on dual therapy, the patient is likely to
makes good pharmacologic sense, as each improves insulin
need a more intensive insulin program. Also, there is no evi-
resistance primarily in a different tissue. Also, there may be
dence that bedtime glargine insulin results in better glycemic
some potential for limiting weight gain with TZDs when
control than bedtime neutral protamine Hagedorn (NPH)
used with metformin. Furthermore, with the data on preser-
insulin, although there is certainly less hypoglycemia with
vation of β-cell function, a TZD may
help preserve insulin
the former.61 Use of glargine insulin increases costs by 65%
secretory capacity and thus delay secondary failure of oral
versus NPH insulin. As is noted in table 3, triple oral agent
agent therapy.35,37,38 As well, this combination may allow
therapy costs over twice as much as SU and metformin plus
for tighter glycemic control without the risk of severe
bedtime NPH insulin for a similar reduction in HbA1c.
hypoglycemia that using an SU might bring. Lastly, the beneficial effects on surrogate markers of CVD cannot help
Second, if insulin is started, which oral agent(s) should be
but make one think of the potential
benefit of TZDs beyond
stopped? This will depend on the type of insulin program
lowering glucose. What might be the potential cost-benefit
contemplated. If bedtime insulin is chosen, then daytime oral
of early use of TZD therapy, if they are shown to prevent
agents should be continued. However, if a more intensive
cardiovascular events and/or deaths?
insulin program is started, then three options should be con-sidered: (1) continue both the SU and metformin, (2) stop
Triple oral therapy or insulin initiation?
the SU and continue metformin, (3) discontinue both oral
Perhaps one of the most difficult decisions in the management
agents. Provided appropriate adjustments in insulin are made,
of type 2 DM has become whether to add a third oral agent
each of these three options will likely result in a similar
or to start insulin therapy in an uncontrolled patient. This
improvement in HbA1c. The cost is surprisingly similar as
has only become an issue since the release of the TZDs
well, owing to the differences in total insulin dose that will
several years ago. As mentioned previously, there may be
be needed to achieve control (i.e., continuing oral agents
several reasons why these agents should be used earlier in
will result in less insulin being needed) (table 3).62,63
the course of treatment than is typically the case. TZDs have
Continuation of metformin makes intuitive sense, as its
now been primarily used as third line agents and they will be
mechanism compliments that of insulin and tends to lessen
discussed as such in this setting. There are three key issues
any weight gain that might occur. On the contrary, an SU
that need considering when facing this decision.
works in relatively the same manner as insulin and thus is
Cost comparison of combination agents versus component agents separately.
a Average wholesale price for brand name and maximal allowable cost for generic preparations.
*Glucophage-XR, Glucovance and Metaglip (Bristol-Myers Squibb Company, Princeton, NJ); Avandamet (GlaxoSmithKline, Research Triangle Park, NC).
Therapeutic options in type 2 DM
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Cost comparison of triple oral therapy (adding thiazolidinediones) versus institution of various insulin programs in patients uncontrolled on
sulfonylureas (SU) and metformin combination therapy.
HbA1c reduction (%
HbA1c reduction (%)
SU maximal dosec +
metformin 1000 bid
SU maximal dose +
metformin 1000 bid +
TZD maximal dosed
2.5 for responders44
60% response rate44
SU maximal dose +
metformin 1000 bid +
NPH and regular bid or
120 units/daye (70% NPH; 30% short-acting insulin)
NPH and Humalog/NovoLog bid g
metformin 1000 bid +
NPH and regular bid or
82 units/day62,63 (70% NPH: 30% short-acting insulin)
NPH and Humalog/NovoLog bid
SU maximal dose +
metformin 1000 bid +
NPH and regular bid or
46 units/day62,63 (70% NPH; 30% short-acting insulin)
NPH and Humalog/NovoLog bid
a Insulin doses for oral agents plus insulin regimens represent "insulin-sparing" effects of oral agents as described in references noted.
b Average wholesale price for brand name and maximal allowable cost for generic (oral agents ± insulin vials) (syringes included).
c SU (sulfonylurea), Glipizide-GITS 10 mg qd or glimepiride 4 mg qd.
d TZD (thiazolidinediones), pioglitazone 45 qd or rosiglitazone 4 bid.
e Insulin dosage assumes a 100 kg patient requiring 1.2 units/kg/day.
f NPH, neutral protamine Hagedorn.
g Humalog (Eli Lilly and Company, Indianapolis, IN ); NovoLog (Novo Nordisk Pharmaceuticals, Inc., Princeton, NJ).
often discontinued. It should be remembered, that the SU is
common strategies is to employ a twice-daily regimen of an
often still having some, albeit an inadequate, effect on glucose
intermediately-acting insulin mixed with a short-acting
control. If discontinued, the SU effect will dissipate quickly,
insulin (figure 3). Whether self-mixing of insulin or premixed
allowing glucose levels to sometimes rise dramatically. The
formulations are used is a matter of preference, but the
physician should relay this possibility to the patient so as to
author prefers the former for its greater flexibility, which
not mislead them into believing that the insulin is not working
allows tighter control with less hypoglycemia. However,
and they were "better off on pills." This may be particularly
self-mixing of insulin may result in less accuracy. The choice
important in patients who have been very resistant to insulin
of regular insulin versus an insulin analog can be debated.
and in those who are less likely to be compliant with scheduled
Most often this debate centers on cost-benefit issues as each
follow-up. Continuation of both the SU and metformin may
vial of an insulin analog is priced approximately $34 more
be best in these patients. Interestingly, the incremental cost
than regular insulin. As previously mentioned, this incremental
of using fast-acting insulin analogs versus regular insulin
cost becomes less of an issue as oral agents are used with
becomes less as one or more oral agents are continued with
insulin. There is good evidence that both insulin analogs
insulin initiation due to an "insulin-sparing" effect of oral
result in improvements in HbA1c (Humalog, 0.3% to 0.4%
agents (table 3). As β-cell failure progresses, an increase
[Eli Lilly and Company, Indianapolis, IN] and NovoLog,
in exogenous insulin will be required, thus rendering the
0.12% to 0.16% [Novo Nordisk Pharmaceuticals Inc.,
continued use of the SU less cost-neutral.
Princeton, NJ]) when compared to regular insulin.64 Bothanalogs have also been shown to reduce hypoglycemic risk
Lastly, what type of insulin program should be started?
(especially nocturnal hypoglycemia) when compared with
While a complete discussion of insulin options beyond
regular insulin.64 For these reasons the author prefers to use
bedtime dosing only is impossible here, one of the most
CM&R 2003 : 1 (July)
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Weight gain associated with the treatment of type 2 DM
events. The greater a drug's propensity to cause hypo-
Excess body weight and obesity play a large role in the
glycemia, the larger an issue this becomes. Therefore, gly-
development of type 2 DM. Many patients have struggled
buride and insulin are the agents for which this component
unsuccessfully for years to lose weight. Depending on a
of weight gain can be substantial. The weight gain associated
variety of factors patients might be gaining, maintaining, or
with TZDs is a mixture of increased fat mass and fluid
even losing weight when they are diagnosed with type 2
retention.57 Both the incidence of edema and amount of
DM. The weight gain that often occurs in the first year of
total weight gain with TZDs increases from monotherapy
treatment can thus be especially frustrating. The propensity
(4%, 1 to 3 kg) to combination with SU (6%, 2 to 2.5 kg) to
for weight gain differs significantly between treatment options
combination with insulin (15%, 4 to 5.4 kg) (rosiglitazone
with metformin generally being the most weight-neutral.
Insulin and the TZDs are at the other end of the spectrum,
being prone to cause the greatest weight gain. The causes ofweight gain associated with treatment of type 2 DM are
The optimal care for the growing number of patients with
listed in table 4. The distribution of weight gain shows
type 2 DM has been and will remain a complex and difficult
two-thirds representing increased fat mass and one-third lean
task. The importance of optimal control has become clear
body mass.65 The weight-neutral characteristic of metformin
with the results of the UKPDS. The cost of type 2 DM to the
may be due to its ability to decrease energy intake.66
United States healthcare system is enormous. With neweragents now available treatment costs will continue to rise as
The contribution of decreased glycosuria to weight gain can
well. Physicians must critically appraise the true benefits of
be substantial and will be greatest in those with the poorest
newer drugs (including combination agents) from the stand-
baseline control. However, those with the poorest baseline
point of glucose control, side effects, potential non-glycemic
control will improve the most with therapy. For every 100 g
effects and cost. This difficult task is made even more
per day decrease in glycosuria, there is a positive energy
difficult by the endless barrage of information provided by
balance of 400 kcal per day.57 With 1 kg of adipose tissue
pharmaceutical companies to physicians and patients alike.
representing approximately 7,700 kcal, it can take just 3 weeks
It is not acceptable to allow the optimal care of patients with
to gain 1 kg once glycosuria ceases. Data from the UKPDS
type 2 DM to be so confusing as to be impossible for the busy
demonstrated a 2.5 kg weight gain in the intensively treated
clinician to implement. When looked at from the standpoint
group versus the conventional group. The HbA1c difference
of its component parts–insulin resistance and insulin
was 0.9%.14 Thus, one might expect a 2.8 kg (6.16 pound)
deficiency–the management of type 2 DM becomes some-
weight gain for every 1% decline in HbA1c. The increased
what clearer. Furthermore, if one is allowed the opportunity
food intake associated with hypoglycemia may be related to
to truly compare the cost and effectiveness of the newer
the treatment of overt events, stimulation of appetite by mild
agents and combination drugs with more tried agents, the
hypoglycemia and attempts by the patient to prevent future
appropriate choice of therapy becomes more obvious. Thepotential benefits of some newer agents on the cardio-vascular system and on β-cell rejuvenation need to be con-sidered, as well, with the significant burden that CVD andsecondary failure to oral agents represent in the managementof type 2 DM. This review hopes to demystify the managementof type 2 DM from the initiation of oral agents through dual(potentially triple) therapy onto insulin initiation. The morewe can understand about the agents available to us, the betteroff our patients will be.
Thanks to Gary S. Plank, Ph.D., former Manager, SecurityHealth Plan Pharmacy, and Eric Paulsen, Manager, Clinic
Characteristic action profiles of a twice-daily regi-
Pharmacy of Wausau, for helping with drug costs. Thanks
men of an intermediately acting insulin (black line) mixed
also to Marshfield Clinic Research Foundation for providing
with a short acting insulin (gray line).
assistance in the preparation of this manuscript through theservices of Graig Eldred and Alice Stargardt.
Therapeutic options in type 2 DM
CM&R 2003 : 1 (July)
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© The Authors Journal compilation © 2009 Biochemical SocietyEssays Biochem. (2009) 46, 95–110; doi:10.1042/BSE0460007 Polyamine analogues targeting epigenetic gene regulation Yi Huang*, Laurence J. Marton†, Patrick M. Woster¶ and Robert A. Casero, Jr*1*The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Bunting ◊ Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD 21231, U.S.A., †Progen Pharmaceuticals, Redwood City, CA 94065, U.S.A., and ¶Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48202, U.S.A.
Available online at Marine lipid fraction PCSO-524 (lyprinol/omega XL) of the New Zealand green lippedmussel attenuates hyperpnea-inducedbronchoconstriction in asthma Timothy D. MickleboroughCherissa L. Vaughn, Ren-Jay Shei,Eliza M. Davis, Daniel P. Wilhite School of Public Health-Bloomington, Department of Kinesiology, Human Performance and ExerciseBiochemistry Laboratory, 1025 E. 7th St. SPH 112, Bloomington, IN 47404, USA