Oral Agents for Type 2 Diabetes: An Update
Abstract
IN BRIEF
The paradigms for oral pharmacological therapy in type 2 diabetes are
shifting as we attain new insights into the optimal metabolic control in our
patients. Each drug category has unique advantages and disadvantages, and
their proper use necessitates a full understanding of their mechanisms of
action, glycemic and nonglycemic effects, and prescribing indications. This
article reviews published clinical trial data and places them into the context
of contemporary, rational therapeutic strategies for this increasingly common
condition.
Type 2 diabetes is a multifactorial metabolic disease characterized
by abnormalities at multiple organ sites. These defects include insulin
resistance and insulin
deficiency.1,2
The former is primarily represented by decreased insulin-stimulated glucose
uptake in skeletal muscle, augmented endogenous glucose production
(predominately in the liver), and enhanced lipolytic activity in
fat.3 The latter is
an apparent progressive process with both functional defects in islet cell
function and, eventually, apparent loss of β-cell
mass.4,5
These defects are intimately linked, with derangements in one system
exacerbating those in the
others.6
Understanding the defects is important, because addressing them forms the
cornerstone of current and future therapy for this disease.
Several studies, including the U.K. Prospective Diabetes Study (UKPDS),
have now unequivocally shown the benefits of tight glucose control for
patients with
diabetes.7-9
In these studies, microvascular complications were significantly and
consistently reduced in the more aggressively controlled groups of patients.
As a result, various professional organizations have proposed increasingly
stringent metabolic targets for their
management.10,11
The extent to which glycemic control affects macrovascular end points, which
is the major cause of death in patients with diabetes, remains incompletely
understood. Most studies have yet to show definitive benefit. Potential
explanations for this discrepancy include study methodology, the potential
influence of the degree and timing (postprandial versus fasting) of glucose
lowering, or the failure to adequately address insulin resistance in studies
published to date. Several investigations are underway to address these
issues.
At present, when lifestyle changes fail to reduce glucose levels to the
desirable range, the conventional approach is to begin therapy with an oral
antihyperglycemic agent. In
2002,12 we reported
a systematic review of oral agents for type 2 diabetes, in which we assessed
the efficacy of these drugs, both as monotherapy and in combination, and
discussed evidence-based treatment strategies. Now, 3 years later, with a >
50% increase in the number of published trials in this area, we reassess the
literature. Have there been any new developments in this field that might
alter the therapeutic approach to this increasingly common disease?
METHODS
A MedLine search was performed to identify all English-language articles of
randomized, controlled, clinical trials involving currently and previously
available oral agents for type 2 diabetes published after our initial report.
As in our earlier analysis, studies were included if they met the following
criteria: study period of at least 3 months, minimum of 10 subjects in each
group at the conclusion of the study, and hemoglobin A1c (A1C)
reported as a major end point. Studies were excluded if they involved insulin,
triple oral agent combinations, or investigational drugs, or if the study was
limited to a specific subpopulation of type 2 diabetic patients.
FINDINGS
There remain five classes of oral antihyperglycemic drugs approved by the
U.S. Food and Drug Administration (FDA).
Sulfonylureas
Sulfonylurea (SU) drugs (e.g., glyburide, glipizide, and glimepiride)
improve glucose levels by stimulating insulin secretion by the pancreatic
β-cell,13 with
elevated circulating insulin levels partially overcoming peripheral insulin
resistance. It is well recognized, however, that with time, patients on SU
monotherapy experience a progressive loss of glucose control. Because of this,
the question of islet cell “burnout” has been raised. This same
phenomenon, however, is noted in patients taking metformin, a drug that does
not increase insulin
secretion.14
Therefore, β-cell failure may simply be a fundamental feature of type 2
diabetes itself that is not substantially affected by the type of therapy
used.
Treatment with SU agents generally yields a mean absolute A1C reduction of
1-2%.9,15,16
Several published SU studies completed since our original report was published
confirm these points (Tables 1
and
2).17-20
SU agents are effective both as monotherapy and in combination with agents
that have different mechanisms of antihyperglycemic action
(Table 3).
Table 1.
Antidiabetic Oral Agent Monotherapy: Published, Randomized, Controlled
Clinical Trials
Table 2.
Antidiabetic Oral Agent Monotherapy: Published, Randomized, Head-to-Head
Trials
Table 3.
Antidiabetic Oral Agent Combination Therapy: Published, Randomized,
Controlled Trials
Side effects of SUs include weight
gain9,15,21,22
and
hypoglycemia.9,21,23
Weight gain is of particular concern, given that patients are often obese
before therapy initiation. Hypoglycemia risk becomes a more important issue as
patients' overall glucose control approaches the normal range. During the past
several years, the cardiology community has become disquieted because of the
potential effect of SUs on myocardial ischemic
preconditioning.24
The actual importance of this issue in clinical practice remains unclear, but
it has likely been exaggerated.
There are no new outcomes data on vascular end points from prospective
clinical trials. In some retrospective
analyses,25-27
but not in
others,28-30
worse cardiovascular outcomes have been observed in groups of patients taking
SU agents compared to groups taking metformin or thiazolidinediones (TZDs).
Without prospective data, it is not possible to make firm conclusions,
especially in light of data from previous randomized studies showing no
significant increases or decreases in macrovascular risk in SU-treated
patients, despite an apparent benefit on microvascular end
points.9
Non-SU Secretagogues (Meglitinides)
Drugs in this class work similarly to SU agents but have a more rapid onset
and shorter duration of action. As a result, insulin secretion is stimulated
to a greater extent immediately after administration. When drug ingestion is
timed with meals, the result is more physiologically appropriate control of
postprandial glucose concentrations. The benefit of this effect remains
unclear, although epidemiologically, postprandial hyperglycemia is more
closely related to cardiovascular morbidity than is fasting glucose.
There are efficacy differences between the two agents within this group,
repaglinide and nateglinide. The former has an A1C-lowering effect similar to
most other antihyperglycemic agents in both placebo-controlled and
head-to-head
trials,31-35
whereas the latter appears to be less
efficacious36-39
(Tables 1 and
2). Both are approved for use
as monotherapy and in combination with most other oral agent classes
(Table 3).
Side effects are otherwise similar to other secretagogues, including weight
gain and hypoglycemia. These likely occur to a lesser degree than with SUs.
Meglitinides must also be taken shortly before each meal and therefore have a
more frequent dosing schedule than most other agents. Their cost is generally
higher than that of SUs.
Long-term outcomes data are still unavailable for this drug class. However,
the effect on long-term complication rates is likely to be at least similar to
that observed with SUs. It is unlikely that such long-term outcomes studies
will ever be conducted.
Biguanides
Metformin, a biguanide, acts mainly by decreasing hepatic glucose
production40,41—primarily
gluconeogenesis—probably through effects on AMP-kinase. Circulating
glucose levels are thereby reduced. Improved peripheral insulin resistance may
also occur, but study results are
inconsistent.40,42-44
Metformin is commonly referred to as an “insulin sensitizer,”
because glucose levels improve without stimulation of insulin secretion.
Notably, metformin as monotherapy remains the only agent associated with
the potential for weight
loss.40,42,45
Other nonglycemic benefits have been reported, including modest lowering of
lipid
levels,46,47
and improvements in
fibrinolysis,47
inflammatory markers, and endothelial
function.48
Numerous studies during the past several years have continued to
demonstrate a benefit of metformin on these cardiovascular risk
markers.49 In fact,
to date, metformin is the only oral antihyperglycemic agent shown to reduce
macrovascular events in patients with type 2 diabetes, in a relatively small
substudy of the UKPDS involving overweight
subjects.50 When
the drug was added to the regimens of patients no longer responding adequately
to SUs, there was a puzzling increase in mortality, an association that
remains essentially
unexplained.50 Such
a finding appeared to be confirmed in a more recent retrospective
analysis.51 Another
group of investigators has suggested a cardiovascular benefit in patients
undergoing percutaneous coronary
intervention.52
In placebo-controlled trials, metformin consistently lowers A1C by
1-2%.19,46,50,53-58
Trials published since our original report confirm that this drug, while
having a unique mechanism of action, reduces A1C to a similar degree as most
secretagogues59,60
(Tables 1 and
2). Metformin is approved for
use alone or in combination with all other antidiabetic agents
(Table 3). It is also gaining
in popularity as a treatment option for women with polycystic ovary syndrome
and has been demonstrated by multiple investigators to improve ovulatory
capacity and metabolic parameters in this group of insulin-resistant
women.61-63
Since our original report, the results from the Diabetes Prevention
Program64 have also
been published. Metformin was used as one strategy to prevent or delay the
development of type 2 diabetes in one arm of this study involving patients
with impaired glucose tolerance. The relative risk of progressing to diabetes
in metformin-treated patients was reduced by
31%.64 While less
impressive than the 58% risk reduction with lifestyle change, such data have
given encouragement to the notion of using pharmacological therapy in patients
with prediabetes, at least in the subset who cannot or will not undertake a
diet and exercise program.
Gastrointestinal side effects of metformin are
common42 but can be
minimized by slow dosage titration. Because of the rare risk of lactic
acidosis, several contraindications limit this drug's use, including renal and
liver dysfunction, heart failure, dehydration or hemodynamic compromise, and
alcohol abuse. Several studies have described a surprising proportion of
metformin-treated patients with active contraindications for its
use.65-67
Despite this, complication rates are few, suggesting that current prescribing
guidelines may be overly stringent. In fact, a recent retrospective analysis
involving heart failure patients demonstrated actual improved outcomes in
those treated with this
drug.68
TZDs
TZDs are activators of the nuclear transcription factor peroxisome
proliferator-activated receptor-γ (PPAR-γ) and modulate the
activity of a host of genes that regulate carbohydrate and lipid
metabolism.69
Currently available TZDs are pioglitazone and rosiglitazone.
Most notably, TZDs improve insulin sensitivity and enhance glucose
utilization by adipocytes and skeletal
muscle.70-73
Some investigators have also demonstrated a reduction of hepatic glucose
production,44,72
although not to as significant a degree as with metformin. PPAR-γ is
most highly expressed in fat cells, and TZD therapy is associated with
prominent effects on circulating fat-derived factors that influence insulin
sensitivity, such as free fatty acids, adiponectin, and tumor necrosis
factor-α.74
TZD action in muscle tissue may indeed derive indirectly through these
effects.
Since our original report, many more studies indicate that TZDs have
beneficial effects on a variety of cardiovascular risk determinants, including
cytokines and inflammatory
markers,75-77
lipids,78-81
blood
pressure,78,82,83
endothelial
function,78,84-87
and certain cellular and molecular events that control the atherosclerotic
process.88-91
Recently, pioglitazone has been shown to have better effects than
rosiglitazone on plasma
lipids,92 although
the ultimate role of the lipid changes induced by TZDs remains uncertain,
given these agents' apparent potential widespread vascular benefit.
Provocative data regarding a suppressive effect on carotid intimal media
thickness,93 a
surrogate for atherosclerosis, as well as coronary artery restenosis after
angioplasty94,95
have also emerged.
Long-term outcomes studies with TZDs are not yet available. In some
retrospective analyses thus far presented mainly in abstract form, benefit is
suggested on cardiovascular outcomes, but the data are inconsistent and
fraught with interpretative
challenges.96-99
The results of prospective outcome studies underway will be necessary in order
to determine whether these effects yield measurable clinical benefits and
indeed improve the macrovascular complications of type 2 diabetes.
Recent reports also suggest that TZDs may “preserve”
β-cell function. The most convincing data come from the Troglitazone in
the Prevention of Diabetes
study100 of
diabetes prevention that tested troglitazone or placebo in relatively young
women with a history of gestational diabetes mellitus. Progression to type 2
diabetes was reduced by > 50% in women on active treatment, likely a
reflection of improved β-cell function that accompanied increased insulin
sensitivity. Whether such preservation of insulin secretory capacity occurs in
patients once diabetes is established is less clear. To date, small,
short-term studies suggest benefit on markers of β-cell
function.101-103
Convincing data from long-term clinical trials with adequate methodology are
still lacking.
Published trials since our original report have confirmed that the
A1C-lowering effect of the TZDs is
equivalent104 and
typically in the same range as that achieved by the SUs or metformin, in both
placebo-controlled and head-to-head
studies39,
105-108
(Tables 1 and
2). These agents are also
approved as monotherapy and in combination with most other agents, including
metformin—a combination that is increasingly popular and now available
in a single proprietary product (rosiglitazone/metformin)
(Table 3).
Side effects include weight gain and edema, which have precluded their
widespread use for patients with heart failure. Recently, more concern has
arisen regarding the potential effect of TZDs in heart failure patients. A
consensus statement from the American Diabetes Association and the American
Heart Association addressed this issue and endorsed the FDA's current
recommendation that the drugs not be used in patients with advanced heart
failure symptoms (class III or IV New York Heart Association
classification).109
Caution was also advised in patients with less severe heart failure. In a
recent retrospective study of Medicare beneficiaries, decreased mortality was
observed in diabetic patients prescribed a TZD after a hospitalization for
heart
failure.68
Randomized studies are needed to confirm these data before any change in
practice is considered. Troglitazone, the TZD primarily associated with
idiosyncratic hepatocellular injury, has been off the market for several
years. Although the remaining agents have not been shown to pose a similar
risk, recommendations still exist regarding periodic surveillance of liver
function for patients on TZDs.
α-Glucosidase Inhibitors
α-Glucosidase inhibitors (AGIs) act by inhibiting an enzyme on the
enterocyte brush border that breaks down complex starches, delaying intestinal
absorption of carbohydrate and particularly attenuating postprandial blood
glucose
elevations.110,111
Current members of this drug class include acarbose and miglitol.
In placebo-controlled trials, AGIs have usually been shown to reduce A1C by
only
0.5-1%112-122
and are therefore generally considered less efficacious than other classes.
Additional studies since our last report continue to confirm this trend, both
in placebo-controlled and head-to-head
trials18,58,123-126
(Tables 1 and
2). AGIs are approved for use
as monotherapy and in combination with sulfonylureas and metformin
(Table 3).
Side effects include abdominal bloating and cramping, frequently leading to
cessation of drug use. The AGIs' more modest efficacy and higher incidence of
side effects have limited their widespread use in the United States, although,
interestingly, they remain very popular in other countries, particularly
Germany and Japan.
In post hoc analysis of data from the Study to Prevent Non-Insulin
Dependent Diabetes Mellitus trial, acarbose was observed to have an impressive
effect on the risk of myocardial infarction (hazard ratio =
0.09).127 These
data support the view, based on epidemiological studies, that postprandial
hyperglycemia has a greater influence on cardiovascular outcomes than does
fasting glucose. No long-term outcomes data are available on vascular end
points in type 2 diabetic patients, however.
MONOTHERAPY STRATEGIES
Clinical trial research published since our original report does not compel
any change in the prevailing view that most of the available oral agents are
appropriate as initial therapy, barring, of course, any contraindications that
might exist in specific patient circumstances. Most classes of drugs are
equally efficacious in reducing A1C, with the exception of the AGIs and
nateglinide. This conclusion is now garnered from newer studies, both when a
specific agent is compared to placebo
(Table 1) or when two drugs are
compared to each other (Table
2).
Actual medication choice should incorporate not only consideration of
glucose-lowering efficacy and contraindications, but also the myriad of other
clinical features of individual patients. These include comorbidities, the
capacities and tolerances of the patient, anticipated side effects, the degree
of glucose control desired, concurrent drug therapy, dosing frequency, and
cost.
Most endocrinologists continue to prefer metformin as the optimal
first-line agent, particularly in obese patients, as long as no
contraindications are present. First-line therapy with TZDs is becoming
increasingly popular, but in the absence of convincing outcomes data and in
light of side effects and cost, such a choice cannot yet be considered
evidence based. Cardiovascular outcomes studies and investigations exploring
the effects of TZDs on β-cell function should be available over the next
1-2 years. The results of these may indeed alter recommendations regarding the
optimal initial approach to this disease.
Primary therapy with secretagogues is no longer as popular. In certain
patients, particularly those in whom there appears to be a greater degree of
pancreatic dysfunction as opposed to insulin resistance, or in those with
contraindications for the other agents (e.g., advanced heart failure), their
use as initial therapy is logical. Patients with erratic meal schedules and
those with marked postprandial glucose excursions may do best with the
rapid-acting non-SU secretagogues. The AGIs may best benefit those patients
with mild hyperglycemia, particularly those with demonstrable postprandial
excursions who are able to tolerate the significant side effect profile of
drugs in this class.
COMBINATION STRATEGIES
As discussed above, diabetes is a complex disorder that involves multiple
pathophysiological defects. Data from the UKPDS suggested that a ∼ 50%
loss of β-cell function was already present in newly diagnosed type 2
diabetic
patients.128 As
the disease progresses, further functional decline in β-cell output is
apparent. As a result, only 50% of patients were adequately controlled on
monotherapy 3 years after diagnosis; by 9 years, this figure had fallen to
25%. Thus, combination therapy involving agents with complementary mechanisms
of action is not only logical but frequently necessary to achieve control.
Published trials since our original report confirm the additive beneficial
effects on glucose control of agents from different therapeutic
classes19,33,39,58-60,129-145
(Table 3). Typically, the A1C
reduction resembles the effect of the added individual agent when used as
monotherapy. Few studies, however, suggest an actual “synergistic”
effect. Precisely how various regimens function together metabolically remains
incompletely understood but is an area of great interest that warrants further
inquiry.
Over the past several years, the availability of several combination
products incorporating SUs with metformin or metformin with a TZD have been
marketed. These convenient formulations may enhance compliance. Their
availability raises the potential for starting patients at the outset with two
drugs. Such an approach is logical and will likely result in quicker
achievement of target glucose levels, particularly in those with the greatest
degree of baseline glycemia.
EMERGING THERAPIES
Additional pharmacological agents will likely soon become available for the
management of patients with type 2 diabetes. These include other PPAR-agonists
with additional effects on PPAR-α and PPAR-δ, and consequently
better lipid effects than current
TZDs.146 Several
agents are in late-phase trials, although several others have been dropped at
this stage because of toxicity concerns.
Modulation of the incretin system is another area of active investigation
by several pharmaceutical companies. Incretin mimetics include glucagon-like
peptide-1 agonists and the dipeptidyl peptidase-IV
inhibitors,147,148
which augment endogenous incretin levels. These drugs improve
glucose-dependent insulin secretion while simultaneously suppressing glucagon
secretion, delaying gastric emptying, and decreasing appetite. Modest
decreases in body weight are described with their use.
Obesity, the principle cause of type 2 diabetes, remains an important
target for possible drug therapy. Available antiobesity drugs have limited
effectiveness on body weight; clearly, newer therapeutic options are needed.
One such agent,
rimonabant,149
modulates the endogenous cannabinoid system and appears to be furthest along
in development. We suspect that future weight loss agents with more
substantive effects on body weight will likely play an increasingly important
role in the future therapy of obese type 2 diabetic patients.
CONCLUSIONS
During the past 5 years, oral agent options for patients with type 2
diabetes have remained relatively static, and there is a paucity of new
information from diabetes clinical trials that would significantly affect the
way we should prescribe these drugs. In contrast, over the next several years,
as the results of key clinical trials are revealed, the optimal therapeutic
approach will likely be better defined, specifically regarding the best
initial therapy for drug-naive patients. Such a choice may arise from studies
exploring the cardiovascular and β-cell impact of various agents,
particularly the insulin sensitizers. Other emerging concepts being addressed
by ongoing investigations involve the notion of earlier treatment, perhaps
even in the prediabetic state, more aggressive progression to combination
strategies, and more liberal use of insulin sooner in the disease course.
It is unlikely, however, that any study result will alter the realization
that the ideal drug choice for a specific individual is a complex decision
that needs to be made by each practitioner, taking into account the risks and
benefits of each agent and the requirements, capacities, and unique clinical
features of each patient. Moreover, the actual selection may not be as
important as an overall comprehensive approach to care that involves not only
glycemic management, but also aggressive modification of other cardiovascular
risk factors. To what extent emerging drug classes will affect this
therapeutic approach to type 2 diabetic patients remains unclear.
Footnotes
-
Bonnie Kimmel, MD, is a senior resident in general internal medicine at
the Yale Primary Care Residency Program in Waterbury and New Haven, Conn.
Silvio E. Inzucchi, MD, is a professor of medicine and clinical director of
the Section of Endocrinology at Yale University School of Medicine and
director of the Yale Diabetes Center at Yale-New Haven Hospital in New Haven,
Conn.
-
Note of disclosure: Dr. Inzucchi has served on advisory
boards for Takeda, Pfizer, and Novartis. He has received honoraria for
speaking engagements from Takeda, GlaxoSmithKline, and Bristol-Myers Squibb.
These companies market oral pharmaceutical products for the treatment of
diabetes.
- American Diabetes Association
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