Oral Antihyperglycemic Therapy for Type 2 Diabetes

Abstract

Context Care of patients with type 2 diabetes has been revolutionized throughout
the past several years—first, by the realization of the importance of
tight glycemic control in forestalling complications, and second, by the availability
of several unique classes of oral antidiabetic agents. Deciphering which agent
to use in certain clinical situations is a new dilemma facing the primary
care physician.

Objective To systematically review available data from the literature regarding
the efficacy of oral antidiabetic agents, both as monotherapy and in combination.

Data Sources A MEDLINE search was performed to identify all English-language reports
of unique, randomized controlled clinical trials involving recently available
oral agents for type 2 diabetes. Bibliographies were also reviewed to find
additional reports not otherwise identified.

Study Selection and Data Extraction Studies (63) were included in the analysis if they had a study period
of at least 3 months; if each group contained at least 10 subjects at the
study’s conclusion; and if hemoglobin A1c was reported. When multiple
dosages of a drug were tested, the results of the highest approved dosage
were used. In placebo-controlled trials, hemoglobin A1c data are
presented as the difference between the change in treated vs placebo subjects.

Data Synthesis Five distinct oral drug classes are now available for the treatment
of type 2 diabetes. Compared with placebo treatment, most of these agents
lower hemoglobin A1c levels approximately 1% to 2%. Equivalent
efficacy is usually demonstrated when different agents are compared with one
another in the same study population. When they are used in combination, there
are additional glycemic benefits. Long-term vascular risk reduction has been
demonstrated only with sulfonylureas and metformin.

Conclusions With few exceptions, the available oral antidiabetic agents are equally
effective at lowering glucose concentrations. Their mechanisms of action are
different, however, and as a result they appear to have distinct metabolic
effects. These are reflected in their adverse effect profiles and their effect
on cardiovascular risk, which may influence drug choice.

Epidemiology

Diabetes mellitus affects more than 6% of the US population, with the
great majority having type 2 diabetes mellitus (DM).1
In some older groups, the prevalence of DM and its metabolic forerunner, impaired
glucose tolerance (IGT), approaches 25%.2 Throughout
the past decade, a 30% increase in the prevalence of DM has been recorded
in the United States, with the most dramatic increases in younger individuals.3 When the long-term complications of this disease and
their costs are considered, the implications of these statistics are sobering.4

The importance of blood glucose control in preventing microvascular
complications of DM, such as retinopathy and nephropathy, is now recognized.5-7 Whether such a relationship
exists for macrovascular complications, such as myocardial infarction and
stroke, is less clear.7 Simultaneously, a rapidly
expanding therapeutic armamentarium is now available to treat hyperglycemia
in type 2 DM. The number of oral antihyperglycemic agent classes, each with
its unique mechanism of action, has increased 5-fold throughout the past 6
years—an often confusing increase in new categories of drugs: biguanides, α-glucosidase
inhibitors, thiazolidinediones (TZDs), and nonsulfonylurea insulin secretagogues.

More therapeutic options translate into more complex decision making
for primary care physicians and diabetic patients. In this article I review
the individual oral-agent drug classes and the published evidence demonstrating
their efficacy in lowering glucose concentrations as well as their effectiveness
in preventing diabetic complications.

Methods

A MEDLINE search was performed to identify all English-language articles
of unique, randomized controlled clinical trials involving recently available
oral agents for type 2 DM. Bibliographies were also reviewed to find additional
reports not otherwise identified. Studies (63) were included in the analysis
if they met the following criteria: study period of at least 3 months, each
group containing at least 10 subjects at the study’s conclusion, and hemoglobin
A1c (HbA1c) reported. When multiple doses of a drug
were tested, the results of the highest approved dose were used. In placebo-controlled
trials, HbA1c data are presented by convention as the difference
between the change in treated vs placebo subjects.

Pathogenesis of type 2 dm

Knowledge of the pathogenesis of type 2 DM is important in understanding
the appropriate role for each oral-agent class. Type 2 DM is a complex metabolic
disorder resulting from relatively decreased pancreatic insulin secretion
and variable contributions of decreased insulin action, or insulin resistance,
in target tissues, mainly muscle and the liver.8,9
Insulin resistance is first demonstrated in skeletal muscle, in which higher
concentrations of insulin are necessary to allow glucose to enter cells. Peripheral
insulin resistance predicts the development of type 2 DM9,10
and is detected in normoglycemic first-degree relatives of patients with type
2 DM.11-13 It
is influenced by both genetic and environmental (eg, obesity) factors. Insulin-resistant
individuals frequently exhibit a constellation of other characteristics, including
visceral obesity, dyslipidemia, hypertension, hyperinsulinemia, impaired fibrinolysis,
endothelial dysfunction, hyperuricemia, vascular inflammation, and premature
atherosclerosis.14 They are said to have the
metabolic syndrome,15 or insulin resistance
syndrome, emphasizing the presumed central pathogenic role of insulin resistance.

Initially, in the face of insulin resistance, compensatory increases
in pancreatic insulin secretion are able to maintain normal glucose concentrations.
However, as the disease progresses, insulin production gradually diminishes,
leading to progressive stages of hyperglycemia. Hyperglycemia is first exhibited
in the postprandial state, since uptake by skeletal muscle is the metabolic
fate of the majority of ingested carbohydrate energy, and then during fasting.
As insulin secretion decreases, hepatic glucose production, normally attenuated
by insulin, increases. This increase is primarily responsible for the elevation
of fasting glucose levels in patients with type 2 DM. Superimposed upon these
mechanisms is the well-recognized deleterious effect of hyperglycemia itself—glucotoxicity—upon
both insulin sensitivity and insulin secretion.16

Adipose tissue plays an important but often overlooked role in the pathogenesis
of type 2 DM. Insulin resistance is also demonstrated at the adipocyte level,
leading to unrestrained lipolysis and elevation of circulating free fatty
acids. Increased free fatty acids, in turn, further dampens the insulin response
in skeletal muscle17,18 while
further impairing pancreatic insulin secretion as well as augmenting hepatic
glucose production (“lipotoxicity”).19

Therefore, type 2 DM results from coexisting defects at multiple organ
sites: resistance to insulin action in muscle, defective pancreatic insulin
secretion, and unrestrained hepatic glucose production, all of which are worsened
by defective insulin action in fat (Figure
1). These pathophysiological lesions are to blame for the development
and progression of hyperglycemia. They are also the primary targets for pharmacological
therapy.

The importance of glycemic control

The American Diabetes Association’s recommended targets for glycemic
control include a preprandial blood glucose level of 80 to 120 mg/dL (4.4
to 6.7 mmol/L), a bedtime blood glucose level of 100 to 140 mg/dL (5.6 to
7.8 mmol/L), and an HbA1c level of less than 7%.20
More stringent guidelines21 have recently been
offered by the American College of Endocrinology and the American Association
of Clinical Endocrinologists: preprandial blood glucose levels less than 110
mg/dL (6.1 mmol/L), 2-hour postprandial glucose levels less than 140 mg/dL
(7.8 mmol/L), and HbA1c levels at 6.5%. These recommendations are
based on findings from 3 landmark studies: the Diabetes Control and Complications
Trial,5 the Kumamoto Study,6
and the United Kingdom Prospective Diabetes Study (UKPDS),7
which have shown unequivocally that maintaining blood glucose concentrations
as close to normal as possible in both type 1 and type 2 DM decreases the
incidence of microvascular complications.

Nonpharmacological Therapy

Diet, exercise, and weight loss are at the center of any therapeutic
program. Not only do these lifestyle modifications lower blood glucose concentrations,
but also they ameliorate many of the frequently coexisting risk factors for
cardiovascular disease. Unfortunately, most patients are unable to achieve
adequate control with lifestyle interventions alone, which should not detract
from their critical role, since they enhance the effectiveness of medical
regimens. A controlled-energy diet and regular aerobic exercise are therefore
recommended for the majority of patients with type 2 DM, who are usually overweight.22,23

Pharmacological Therapy

Sulfonylureas. Sulfonylurea (SU) drugs have been available in the United States since
1954. Second-generation SUs (glyburide, glipizide, and glimepiride) are more
potent and probably safer than first-generation SUs (chlorpropamide, tolbutamide,
acetohexamide, and tolazamide) but essentially of equal efficacy.24 The SUs bind to the SU receptor, found on the surface
of pancreatic beta cells. This interaction leads to a closure of voltage-dependent
potassium adenosinetriphosphate (KATP) channels, facilitating cell
membrane depolarization, calcium entry into the cell, and insulin secretion.25 Thus, SUs allow for insulin release at lower glucose
thresholds than normal. They partially reverse the attenuated insulin secretion
that characterizes type 2 DM. Understandably, in the face of SU therapy, circulating
insulin concentrations are increased.26 As
a result, and despite the presence of insulin resistance, glucose concentrations
fall. The possibility that such agents may also directly enhance peripheral
glucose disposal (ie, decrease insulin resistance) has also been raised.27,28 However, the peripheral effects of
SUs are most likely secondary to a reduction in glucotoxicity.

When compared with placebo, SU therapy leads to a mean decrease in HbA1c of approximately 1% to 2% (Table
1).7,29,30
One study31 demonstrated a more impressive
change, but the rise in HbA1c level experienced by the placebo
group was greater than usual, reaching 2%. Current agents are equally efficacious32-37
and vary subtly, such as in their metabolism and duration of action. The newest
member of this class, glimepiride, binds less avidly in cardiac tissues, which
contain KATP channels similar to those of beta cells. Glimepiride,
therefore, may reduce ischemic preconditioning less than the other SUs do,38 the clinical importance of which is unclear. In general,
there is no consistent additional benefit on coexisting conditions, such as
elevated lipid levels or blood pressure. Given the epidemiological association
between hyperinsulinemia and cardiovascular disease, some have raised concerns
that SUs increase cardiovascular morbidity.39,40
An early trial by the University Group Diabetes Project,41
which explored the effectiveness of oral agents vs insulin, found increased
cardiovascular mortality in the cohort of patients randomized to SUs. Widespread
criticism of the project’s methodology has placed the validity of its findings
in doubt.42 In the more recent UKPDS, which
had a better experimental design, increased mortality was not shown in SU-treated
subjects.7 Given these agents’ mechanism of
action and frequent loss of efficacy over time, another concern is their potential
to exhaust beta cell function. However, as demonstrated in the UKPDS, the
inexorable decline in beta cell function may be an underlying characteristic
of the diabetic state itself, independent of treatment modality. Of more practical
concern, SU therapy is associated with 2 common adverse effects. The first
is weight gain, typically from 2 to 5 kg, problematic in a group of patients
frequently already overweight.7,25,28,29
The second is hypoglycemia, most likely to affect the elderly, those with
worsening renal function, and those with irregular meal schedules.7,25,32

In the UKPDS, 4209 patients newly diagnosed with type 2 DM were randomized
to either intensive (medication) or conventional (diet) treatment and observed
for approximately 10 years. The intensive-treatment group underwent a subsequent
randomization to primary therapy with SU or insulin. When compared with conventional
therapy, intensive treatment was associated with a decreased risk of predominantly
microvascular complications, including a 12% reduction in any diabetes-related
end point (P = .03) and a 25% reduction in all microvascular
end points (P<.001). There was no significant
effect on diabetes-related death or on all-cause mortality, however, and there
was only a trend toward a small effect (−16%) on the risk of myocardial
infarction (P = .05).7
Overall, there were no significant differences between SU-treated subjects
and those treated with insulin. One might argue that improved glycemic control
from SUs did not significantly decrease macrovascular risk because this effect
was negated by the opposing effect of hyperinsulinemia.

Optimal dosing of each member of this class varies. As a general rule,
however, glucose-lowering effect plateaus after half the maximal recommended
dose is reached.30,43 Most agents
undergo metabolism by the liver and are cleared by the kidney. Therefore,
they must be used cautiously in those with advanced forms of either hepatic
or renal impairment. Sulfonylureas are approved for use as monotherapy and
in combination with all other oral agent classes (except the non-SU secretagogues)
and insulin.

Biguanides. Although available internationally for decades, metformin, a biguanide,
was not released in the United States until 1995.44
An earlier biguanide, phenformin, was removed from the market in the 1970s
because of an association with lactic acidosis.45
In contrast to the SUs, metformin does not stimulate insulin secretion.46,47 The precise mode of action of metformin
remains somewhat controversial, but its predominant effect is to reduce hepatic
glucose production in the presence of insulin.48,49
It is therefore considered an insulin sensitizer. Increased peripheral glucose
disposal has also been measured,44,50
although this is most likely a secondary phenomenon caused by lowering of
glucotoxicity and not a direct effect of the drug itself.48,51

In placebo-controlled trials, metformin’s ability to lower HbA1c is similar to that of SUs (ie, −1% to 2%, placebo-adjusted)
(Table 1).52-59
When compared with SUs in head-to-head trials, metformin’s glucose-lowering
effect is generally equivalent (Table 2).60-63
Metformin monotherapy, however, is associated with weight loss (or no weight
gain) and much less hypoglycemia than SU therapy.44,47,48
Because of the lack of beta cell stimulation, circulating insulin concentrations
tend to decline, which may provide a cardiovascular advantage. Other nonglycemic
benefits have also been ascribed to metformin, such as decreases in lipid
levels (low-density lipoprotein cholesterol and triglycerides)52,64
and the antifibrinolytic factor plasminogen activator inhibitor 1.64 Recently, an amelioration in vascular reactivity
or endothelial function has also been demonstrated.65
The only study that has examined the overall effectiveness of metformin on
long-term complications is the UKPDS, where the agent was included in the
randomization schema with conventional diet therapy and intensive SU-insulin
treatment in a subgroup of overweight patients. Those who received metformin
experienced less hypoglycemia and weight gain than those who received SUs
or insulin. With a similar HbA1c reduction observed in the other
intensively treated subjects, more impressive risk reduction was noted in
the primary aggregate end points. Metformin-treated subjects, for instance,
had a 32% reduction in any diabetes-related end point (P = .02), 42% less diabetes-related deaths (P
= .02), and a 36% reduction in all-cause mortality (P
= .01). Specifically, compared with that of the conventional group, the risk
of myocardial infarction was reduced by 39% (P =
.01); of all macrovascular end points, by 30% (P
= .02).58 Individual and total microvascular
end points were not significantly reduced, however, presumably because of
the relatively small sample size, since there were no differences in microvascular
outcomes between the metformin and the SU–insulin-treated groups. These
important findings suggested that the manner in which glucose levels are lowered
by antidiabetic agents might uniquely influence certain outcomes. In addition,
metformin has been shown to improve ovulatory function in insulin-resistant
women with polycystic ovarian syndrome and, most recently, to decrease the
progression from IGT to type 2 DM.

Adverse effects of metformin therapy include gastrointestinal distress,
such as abdominal pain, nausea, and diarrhea, in up to 50% of patients.44 The frequency of these adverse effects can be minimized
with food consumption and slow titration of dose; the need to discontinue
therapy is uncommon. The optimal dosage in most patients appears to be 2000
mg/d.56 The risk of lactic acidosis is approximately
100 times less than that with phenformin therapy: approximately 1 in every
30 000 patient-years.66 The drug must
be avoided in those who are at increased risk for lactic acidosis, such as
those with renal impairment (serum creatinine level ≥1.5 mg/dL [132.6 µmol/L]
for men or ≥1.4 mg/dL [123.8 µmol/L] for women), in whom metformin
clearance is diminished. Other contraindications include hepatic dysfunction,
congestive heart failure, metabolic acidosis, dehydration, and alcoholism.
It should be temporarily withheld in patients with virtually any acute illness
and those undergoing surgery or radiocontrast studies. The need for additional
therapies after several years of use was also demonstrated in metformin-treated
subjects in the UKPDS, so beta cell failure also occurs in patients who are
treated with this agent.67 It is approved for
use as monotherapy and in combination with SUs and other secretagogues, TZDs,
and insulin.

α-Glucosidase Inhibitors. The α-glucosidase inhibitors (AGIs; eg, acarbose and miglitol)
were introduced in 1996. Their mechanism of action is unique, and this is
the sole drug class not targeted at a specific pathophysiological defect of
type 2 DM. An enzyme in the brush border of the proximal small intestinal
epithelium, α-glucosidase serves to break down disaccharides and more
complex carbohydrates. By the competitive inhibition of this enzyme, the AGIs
delay intestinal carbohydrate absorption and mitigate postprandial glucose
excursions.68,69

The efficacy of AGIs is considerably less than that of either SUs or
metformin, with an average HbA1c lowering effect of approximately
0.5% to 1% compared with that of placebo-treated subjects (Table 1).57,70-80
Not surprisingly, their greatest effect is on postprandial glucose levels,
whereas the effect on fasting blood glucose levels is small.57,70-80
In a comparative study, acarbose had about half the glucose-lowering effect
of an SU, tolbutamide.81 Several other head-to-head
trials have claimed efficacy equal to that of SUs82,83
and metformin,57 but in 2 of these,57,82 the dose of the comparator drug was
suboptimal (Table 2).

The AGIs are attractive in that they are essentially nonsystemic and
unassociated with hypoglycemia and weight gain. Nonglycemic benefits include
small reductions in triglycerides and postprandial insulin levels.69,84 The targeting of postprandial glucose
may provide a theoretical advantage because postprandial hyperglycemia has
been linked with cardiovascular mortality.85
However, there have been no studies that have examined long-term effectiveness
of these agents in reducing chronic complications. In addition, other classes
of antidiabetic drugs reduce overall glucose levels, including those in the
postprandial period.

Adverse effects of AGIs include flatulence, abdominal discomfort, and
diarrhea, frequently leading to discontinuation of the drug. The AGIs are
rarely used as monotherapy because of their comparatively mild efficacy. They
are approved for use as monotherapy and in combination with SUs. One caveat
regarding AGI therapy (specifically, when combined with secretagogues or insulin)
is the requirement that hypoglycemia be reversed by consuming glucose itself,
as opposed to more complex carbohydrates.

Thiazolidinediones. In 1997, troglitazone, a TZD, was introduced in the United States. It
was later removed from the market because of rare idiosyncratic hepatocellular
injury.86 This novel class of drugs, currently
represented by rosiglitazone and pioglitazone, has a unique mechanism of action
that remains incompletely understood. Thiazolidinediones are pharmacological
ligands for a nuclear receptor known as peroxisome-proliferator-activited
receptor gamma. When activated, the receptor binds with response elements
on DNA, altering transcription of a variety of genes that regulate carbohydrate
and lipid metabolism.87 The most prominent
effect of TZDs is increased insulin-stimulated glucose uptake by skeletal
muscle cells.88-91
Thus, these agents decrease insulin resistance in peripheral tissues. Hepatic
glucose production is decreased, although perhaps only at the highest doses.51,90 Peroxisome-proliferator-activited
receptor gamma activation also reduces lipolysis and enhances adipocyte differentiation.
It is interesting to consider that the receptor is most highly expressed in
adipocytes, while expression in myocytes is comparatively minor. Therefore,
the increase in glucose uptake by muscle may largely be an indirect effect
mediated through TZD interaction with adipocytes.92
Candidates for the intermediary signal between fat and muscle include leptin,
free fatty acids, tumor necrosis factor α, adiponectin, and the more
recently isolated resistin.93

As with metformin, the TZDs do not stimulate pancreatic islet cells
to secrete more insulin. Indeed, insulin concentrations are usually reduced,
perhaps to an even greater extent than with metformin.56,57
Thiazolidinediones enhance the responsiveness and efficiency of beta cells,
presumably by decreasing glucose and free fatty acid levels, both of which
have deleterious effects on insulin secretion.94
Preliminary data also suggest that this drug class may actually prolong beta
cell survival.95,96

In placebo-controlled trials, TZDs generally lower HbA1c
as much as SUs and metformin do,97-101
and more than AGIs do (Table 1).
Head-to-head studies have been performed on TZDs vs metformin102,103
and SUs,104 with equivalent reductions in HbA1c (Table 2). No long-term
outcome studies on microvascular end points are available. In relatively short-term
studies, TZDs appear to lower microalbumin excretion, perhaps a manifestation
of their beneficial effect on endothelial function.100,105
Since TZDs decrease insulin resistance and because the latter is associated
with macrovascular disease, some have wondered whether these drugs might provide
cardiovascular protection.38,106,107
Preliminary evidence suggests that this notion may by justified.108

In addition to their ability to lower insulin levels, the TZDs also
have certain lipid benefits. High-density lipoprotein cholesterol concentrations,
for instance, increase with TZD therapy and triglyceride concentrations frequently
fall.101,104 The effect on low-density
lipoprotein cholesterol concentrations is more variable, with increases reported
with some,104,109 but not all,101 agents. Any rise in low-density lipoprotein cholesterol
concentrations may be due to a shift from small and dense to large and buoyant
low-density lipoprotein particles, which are less atherogenic.110,111

Thiazolidinediones also slightly reduce blood pressure,112
enhance fibrinolysis,113 and improve endothelial
function.114 These agents also appear to decrease
in vitro vascular inflammation and vascular smooth muscle cell proliferation,115 both important elements in the atherosclerotic process.
Animal data suggest an antiatherosclerotic effect.116
However, whether such nonglycemic effects will eventually translate into benefits
on actual clinical end points remains unclear. Only 3 human studies have examined
more than just biochemical effects related to vascular disease. In a Japanese
investigation troglitazone reduced intimal-medial thickness of carotid arteries
in diabetic patients, as measured by ultrasound.117
Similar changes were more recently reported with pioglitazone by the same
group.118 In another study, troglitazone decreased
neointimal proliferation after angioplasty.119
Several studies examining the clinical implications of these findings are
under way, although data most likely will not be available for several more
years. The 2 TZDs currently available, rosiglitazone and pioglitazone, appear
to have similar efficacy on glycemia.120

Adverse effects of TZDs include weight gain, which can be as great or
greater than that with the SUs. Weight gain appears to involve mostly peripheral
subcutaneous sites, with a reduction in visceral fat depots,121
the latter being better correlated with insulin resistance. Edema can also
occur. Both weight gain and edema are more common in patients who receive
TZDs with insulin. Anemia may also occur infrequently. Although the Food and
Drug Administration still recommends periodic measurement of hepatic function,
the available TZDs, unlike troglitazone, have not been convincingly associated
with liver injury. Patients with advanced forms of congestive heart failure
and those with hepatic impairment should not receive TZDs. Thiazolidinediones
are the most expensive class of antidiabetic medication and are indicated
as monotherapy and in combination with metformin, SUs, and insulin (pioglitazone
only).

Non-SU Secretagogues. The mechanism of action of the non-SU insulin secretagogues (repaglinide
[a benzoic acid derivative] and nateglinide [a phenylalanine derivative])
is similar to that of SUs: interaction with voltage-dependent KATP
channels on beta cells. They are distinguished from the SUs by their short
metabolic half-lives, which result in brief episodic stimulation of insulin
secretion.122 There are 2 important consequences
from this difference. First, postprandial glucose excursions are attenuated
because of greater insulin secretion immediately after meal ingestion.123 Second, because less insulin is secreted several
hours after the meal, there is decreased risk of hypoglycemia during this
late postprandial phase.124 One agent, nateglinide,
has little stimulatory effect on insulin secretion when administered in the
fasting state.125 Thus, nateglinide may enhance
meal-stimulated insulin secretion more than other secretagogues do. Efficacy
of repaglinide is similar to that of SUs,126,127
whereas nateglinide appears to be somewhat less potent a secretagogue (Table 1).128
Three comparative trials129-131
(Table 2) of repaglinide vs SU
have been published, each showing equal lowering of glucose levels. In single
studies, the efficacy of repaglinide was equal to that of metformin132 but greater than that of troglitazone.133
In 1 study, nateglinide was less efficacious than metformin.134
These drugs have not been assessed for their long-term effectiveness in decreasing
microvascular or macrovascular risk. Adverse effects include hypoglycemia
and weight gain, which are probably less pronounced than that caused by the
SUs.129 One disadvantage of this drug category
is the frequent dosing schedule required with meals. Repaglinide and nateglinide
are hepatically metabolized and renally cleared and should be use cautiously
when function of the liver and kidneys is impaired. They are approved for
use either as monotherapy or in combination with metformin.

Monotherapy Recommendations

Given the myriad therapeutic options available for type 2 DM, how does
the physician choose the best drug for a specific patient? Except for the
AGIs and nateglinide, which are generally less effective, each of the other
drugs will lead to a similar reduction in HbA1c. Table 3 summarizes the relative advantages and disadvantages of
different drug classes. Does one drug class hold an advantage over the others?
Because metformin is the only drug associated with weight loss, or at least
weight neutrality, it has become the most widely prescribed single antihyperglycemic
drug and is generally regarded as the best first-line agent, at least in the
obese patient without contraindications for its use. Its favorable performance
in the UKPDS58 supports this approach. In addition,
the virtual lack of hypoglycemia makes metformin therapy an attractive option,
particularly in patients whose control is approaching the euglycemic range.

The precise role for the insulin secretagogues is evolving. Their association
with hypoglycemia and weight gain remains problematic, and concerns regarding
hyperinsulinemia and beta cell exhaustion persist. Although cost-effective
in terms of glucose lowering effect, these agents are being used less as first-line
therapy. They remain an important element of combination regimens. Even in
an era with increasing emphasis on the role of insulin resistance in type
2 DM, insulin deficiency remains a critical pathophysiological target of therapy.135,136 In addition, some consider them
the best first-line agents in nonobese patients who have type 2 DM and may
exhibit more pancreatic secretory dysfunction than insulin resistance.137 Although metformin’s benefits in reducing cardiovascular
end points were demonstrated solely in overweight patients in the UKPDS, its
effect on lowering glucose levels is not predicted by body weight.52,62 (In general, the predictors of response
to other drug classes have not been well studied. In a meta-analysis, the
best responders to TZD therapy had the highest C-peptide concentrations, suggesting
greater insulin resistance, more preserved beta cell function, or both.)138

The niche for the non-SU secretagogues is also unclear. They may be
preferred in those who require secretagogue therapy and have irregular meal
schedules. However, their use must be balanced with their increased cost compared
with the now generic SUs and a considerably less convenient dosing schedule.

Although the TZDs are interesting compounds of great promise, there
are no long-term data on microvascular or macrovascular risk. One may presume
that any agent that lowers glucose levels will eventually lead to a similar
microvascular risk reduction as other agents. Indeed, long-term studies of
the impact of the newer agents on microvascular end points are unlikely, given
the now accepted benefit of conventional agents in this regard. An effect
on macrovascular disease is more difficult to predict because of the lack
of convincing data that this disease is necessarily associated solely with
glucose-level control. Evidence is mounting for an antiatherosclerotic potential
for the TZDs,39,106,107
but because of their increased cost, the continued requirement for liver function
test monitoring, and the potential for weight gain and edema, they are not
widely considered the ideal monotherapy choice. Somewhat paradoxically, TZDs
appear to be most effective when used with the earliest forms of diabetes,
such as in the drug-naive patient,98,101
when insulin secretion is still substantial. As more data emerge regarding
beta cell preservation,94,95 which
may be a unique benefit of this class, and cardiovascular risk reduction,
the TZDs or similar drugs may one day emerge as the best first-line agent
for diabetes. However unlike other agents, TZDs may take weeks or sometimes
months to exert their full glycemic effect. Therefore, they are less attractive
when rapid lowering of glucose levels is desired.

In summary, in terms of antihyperglycemic effect alone, there is no
compelling reason to favor one of the major categories of antidiabetic agents
(SUs, biguanides, and TZDs) over another. However, metformin’s performance
in the UKPDS in obese patients, ie, its lack of associated hypoglycemia and
weight gain, make it the most attractive option for obese—if not all—patients
who have type 2 DM but no contradindications for its use. The emerging TZD
class may provide for additional cardiovascular protection for type 2 DM patients,
but TZDs’ cost and adverse-effect profile make them less fitting as monotherapy,
unless metformin is contraindicated or poorly tolerated. The actual choice
of a drug, however, must be based on a variety of clinical factors and individual
patient characteristics, including predisposition to adverse effects, the
degree of hyperglycemia, and cost. The paramount concern of the physician
should be attainment of the best glycemic control with whatever antidiabetic
regimen is well tolerated.

Combination Therapy

Given the multiple pathophysiological lesions in type 2 DM, combination
therapy is a logical approach to its management. The UKPDS clearly demonstrated
that type 2 DM is a progressive disease. After 3 years, for example, type
2 DM in only 50% of patients was adequately controlled with a single drug,
and after 9 years, this percentage had decreased to 25%.139

Each clinical trial that has examined the addition of an oral agent
to that of another class has demonstrated additive HbA1c reduction
(Table 4).104,132,134,140-151
With few exceptions,104 the effect on HbA1c has been similar to the effect from using the added drug as monotherapy
vs placebo. The most popular combinations are SU and metformin, metformin
and TZD, and SU and TZD. Triple combination therapy, typically SU, metformin,
and TZD, improved glycemia in 1 placebo-controlled study152
but is not formally approved by the Food and Drug Administration. Since HbA1c reduction is the overriding goal in all patients, the precise combination
used may not be as important as the glucose levels achieved. There is no evidence
that a specific combination is any more effective in lowering glucose levels
or more effective in preventing complications than another. So the same patient-specific
criteria that go into the decision tree for monotherapy apply when more complex
regimens are constructed. In the UKPDS, however, a group of patients who did
not achieve acceptable control with SU therapy was randomized to the early
addition of metformin. The results of this substudy were somewhat unexpected
in that combination therapy was associated with a 96% increase in diabetes-related
mortality.58 The authors performed an epidemiological
analysis on all subjects who received this combination, and overall, no increased
risk was shown. Because a deleterious effect of such a commonly used combination
is not biologically plausible, avoiding the combination is not recommended.
In fact, a fixed combination tablet containing glyburide and metformin has
recently become available. Combination therapy involving 2 or 3 drug classes
with distinct mechanisms of action will not only improve glycemic control,
but also result in lower overall drug dosing in some settings140
and minimize adverse effects. If glycemic control cannot be attained with
oral agents alone, there should be no hesitation about using insulin either
alone152 or in combination153,154
with oral agents. The latter approach may be preferred, since it leads to
improved glycemic control and a lower insulin dose compared with insulin monotherapy.

Comment

Type 2 diabetes mellitus is a complex disorder associated with significant
health and economic burdens. Keeping blood glucose levels near the normal
range lowers the risk of complications and is an important therapeutic goal.
A number of oral antihyperglycemic agents have been introduced in the United
States during the past several years, each with its own mode of action. They
are equally effective in lowering blood glucose concentrations and HbA1c, except for the AGIs and nateglinide, which in general appear to
be less potent. Only SUs and metformin have been shown to reduce microvascular
complications, with metformin exhibiting additional benefits on macrovascular
risk. Because they lower glucose levels, however, the remaining drug classes
will presumably have a proportionate effect on microvascular complications.
Their effect on macrovascular risk, however, remains unkown. The proper choice
of antidiabetic agent for a patient is based on several factors. Each drug
class has unique adverse effects and prescribing precautions. The popularity
of insulin sensitizers, defined broadly as metformin and TZDs, is increasing,
since these agents avoid the risk of hypoglycemia associated with secretagogue
therapy and allow for the treatment of patients already near the euglycemic
range. Most patients will require combination therapy as their disease progresses.

References

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