Advances in Diabetes
for the Millennium: Drug Therapy of Type 2 Diabetes
Marc Rendell, MD
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Abstract
There are many new
orally administered agents to treat type 2 diabetes. Sulfonylureas and
meglitinides stimulate insulin secretion. Metformin has been joined by
thiazolidinediones to reduce insulin resistance. Disaccharidase inhibitors slow
glucose uptake after a meal. Beta-3 agonists and agents that augment
glucagon-like peptide activity are promising new agents in the effort to not
only control glucose levels but also restrain weight gain. The future treatment
of diabetes will require multiple drugs working in concert to normalize blood
glucose.
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Introduction
In the 1920s, insulin
injections joined dietary treatment and exercise as the cornerstones of therapy
of diabetes. In the early 1950s, the advent of sulfonylureas and phenformin added
an oral route to a reduction of blood sugar levels. The University Group
Diabetes Program (UGDP) was a study originally designed to assess the effect of
these new agents on the vascular complications of diabetes.
Non-insulin-dependent diabetic patients were randomized into groups treated
with a placebo plus diet, a fixed dose of tolbutamide, a fixed dose of insulin,
a fixed dose of phenformin, or a sliding scale of insulin doses on the basis of
fasting glucose levels. At the end of 7 years, the study was stopped when
excess cardiovascular mortality was discovered in the tolbutamide group with
excess overall mortality as well in the phenformin group.[1]
The publication of
the UGDP results led to a ban on the use of phenformin. Sulfonylurea use was not
officially banned, but its use was strongly discouraged in favor of diet and
insulin treatment of diabetes. The furor surrounding the UGDP results dealt a
severe blow to research on antidiabetic pharmaceuticals in the United States.
However, research continued outside the United States, and in the past 10 years
a host of new oral hypoglycemic agents have become available to treat type 2
diabetes. With so many new choices, there is often considerable confusion about
which agent or combination of agents is optimal for a given patient.
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Agents Which
Stimulate Insulin Secretion
Sulfonylureas
stimulate the production and release of insulin by binding to a receptor site
on the membrane of the pancreatic beta cell. Binding blocks the opening of
ATP-dependent potassium channels, which leads to a depolarization of the
membrane, leading to an influx of calcium. These events result in an increased
production of insulin by the beta cell.
The evolution of the
third-generation agents glipizide and glyburide was a major advance over the
older sulfonylureas.[2] They are 20-50 times more potent than previous
sulfonylureas on a milligram basis. They have a longer biological action than
all preceding agents except for chlorpropamide, with a much lower incidence of
adverse reactions, such as hyponatremia and reactions to alcoholic beverages.
They have low protein binding, so that they have fewer drug interactions.
Glimepiride (Amaryl) was developed more recently and differs from glyburide in
several ways.[3] It is more potent, but behaves more like glipizide than
glyburide with a good postprandial insulin response and a lower incidence of
hypoglycemia than glyburide. A single daily dose of 8 mg is maximal, with very
little added benefit from twice-daily administration of this dose level.
The major side effect
of the sulfonylureas is hypoglycemia. Hypoglycemia is usually associated with
reduced oral intake or prolonged exercise, and is more common with
longer-acting sulfonylureas than with short-acting agents, such as tolbutamide.
The newer
meglitinides, although not chemically sulfonylureas, increase insulin
production by a similar mechanism, at the ATP-dependent potassium channels.
They are much shorter-acting. Typically taken at the beginning of a meal, they
induce an insulin surge, which fades rapidly, thus reducing the risk of later
hypoglycemia. Repaglinide was the first such agent introduced.[4] Recently,
nateglinide, a D-phenylalanine derivative that appears to be even
shorter-acting, has been introduced. There is no added insulin release with
these agents over a maximal dose of sulfonylurea. There is a potential
advantage in using these agents in situations in which hypoglycemia may have
significant risk, such as the elderly and renal and coronary disease patients.
The short action of these agents reduces the risk of hypoglycemia, although not
entirely eliminating it. The disadvantage of use of these agents is the need
for multiple daily doses.
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Metformin
Metformin is a
biguanide that has been marketed in Europe for 30 years. It reduces hepatic
glucose production and increases peripheral glucose utilization. The mechanism
of action is still poorly understood.[5] The degree of glucose lowering induced
by metformin in non-insulin-dependent patients is similar to that of
glyburide.[6] Furthermore, when added to glyburide treatment, metformin
produced a further substantial reduction in glucose levels.[7] Additionally, it
decreases the release of free fatty acids from adipose tissue and lowers the
cholesterol and triglyceride levels.
The most serious
complication of biguanide use is lactic acidosis, which can be fatal.
Fortunately, the incidence of lactic acidosis with metformin use is low (1 case
per 33,000 patient-years).[8] The risk of lactic acidosis is increased in
patients with renal disease. A serum creatinine of 1.5 mg/dL is the suggested
upper limit on use of this agent. The risk of lactic acidosis is also increased
with dehydration and with the use of radiologic contrast dye. Metformin should
be stopped at the time of the radiographic contrast procedure and not restarted
for 48 hours. Although lactic acidosis is very rare, a much more common problem
with metformin is a high incidence of gastrointestinal complaints. One out of 3
patients will experience problems ranging from mild heartburn to significant
diarrhea. Patients do tend to become more tolerant of metformin with time, so
that, in some cases, one can reduce the dose and achieve a lower level of
gastrointestinal distress.
Metformin is
contraindicated in congestive heart failure and is relatively contraindicated
in the elderly.
Unlike insulin and
sulfonylurea treatment, metformin does not encourage weight gain. In fact, some
patients lose weight on metformin therapy. Metformin is effective when given
twice daily. An extended-release, once-daily preparation has recently been
introduced.
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Disaccharidase
Inhibitors
Type 2 diabetes
results from resistance to insulin effects coupled with a relative deficiency
of insulin secretion. The most characteristic abnormality of insulin production
is a reduction in the early-phase release of insulin from the pancreas.
Absorption of
carbohydrates requires the eventual breakdown of disaccharides to form single
sugars by the enzymes in the brush border of the small intestine.
Disaccharidase inhibitors, such as acarbose and miglitol, effectively
compensate for defective early-phase insulin release by inhibiting the
breakdown of disaccharides to monosaccharides in the intestinal epithelium.
Consequently, there is delayed and decreased absorption of these sugars.[9,10]
Thus, there is a lower glycemic peak, permitting the diminished early-phase
insulin secretion to cope more effectively with glucose disposal. The result is
a decrease in postmeal glucose peaks in diabetic patients.
The efficacy of
acarbose and other disaccharidase inhibitors is limited by the adverse
reactions caused by a large amount of nonabsorbed disaccharides in the
intestinal tract. This situation is one of effective malabsorption with the
attendant symptoms of flatulence, abdominal discomfort, and diarrhea. As the
dose of the disaccharidase inhibitor is increased, the level of nonabsorbed
disaccharides rises, leading to worsening malabsorption symptoms. However,
increased disaccharide concentration leads to the induction of disaccharidases
in the jejunum and ileum. Eventually, this induction of new enzymes results in
a slower, smoother absorption of disaccharides. The slower absorption is still
effective in reducing postprandial glucose levels, but with fewer malabsorptive
symptoms. Therefore, disaccharidase inhibitors must be started at a very low
dose, with small increments over time. When started at a low dose with slow
increases, the adverse reactions are minimized. Even so, the gastrointestinal
adverse reactions of acarbose or miglitol occur in up to 40% of patients.
Despite these limiting adverse reactions, the disaccharidase inhibitors have an
advantage in terms of safety. They do not cause hypoglycemia. They do not
undergo renal excretion, so that they are safe in patients with a modest
elevation of serum creatinine.
The disaccharidase
inhibitors are effective as single agents for the treatment of diabetes and are
effective in combination with sulfonylureas or insulin.
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Thiazolidinediones
This class of agents,
like metformin, works not by increasing insulin secretion but, rather, by
increasing insulin sensitivity. However, metformin and thiazolidinedones have
different mechanisms of action because they synergistically improve glycemic control
when given together.[11] Thiazolidinediones appear to activate peroxisome
proliferator-activated receptor (PPAR)-gamma, which is involved in the
metabolism of lipids and the differentiation of adipocytes. There is an
interaction with the retinoid X receptor (RXR) to produce an activated
heterodimer.[12]
Unlike other
antidiabetic agents, the thiazolidinediones have a very slow onset of action.
Although effects begin within 2 weeks, the maximal benefit of treatment is not
seen for about 3 months.[13] When combined with insulin or with sulfonylureas,
the onset and peak effect occur more rapidly, perhaps within 4 weeks.[14,15]
Troglitazone was the
first thiazolidinedione to reach the market. Unfortunately, troglitazone showed
hepatic toxicity.[16] In a small number of patients, severe liver damage
occurred. As a result of this liver toxicity, troglitazone was withdrawn from
the market. Rosiglitazone and pioglitazone followed troglitazone. Neither agent
is toxic to the liver.[17] Rosiglitazone is the most potent thiazolidinedione
with a maximal effective dose of 8 mg daily[18] as compared with 600 mg of
troglitazone and 45 mg of pioglitazone. Carcinogenesis has been a concern with
these agents in animal studies. Troglitazone produced lipoangiosarcomas in
mice. Pioglitazone was associated with bladder cancer in rats. Rosiglitazone
has shown no animal carcinogenesis in preclinical studies.
Thiazolidinediones
are effectively used as single agents, but their relatively slow onset of
action means that other agents are generally preferred as the first treatment
of poorly controlled diabetes. Thiazolidinediones are very effective in
combination use with other agents. Rosiglitazone or pioglitazone reduce HbA1c
by about 1% in patients treated with either a maximal dose sulfonylurea or a
maximal dose metformin, or with insulin treatment.[19-23] This same reduction
of HbA1c appears to hold when a thiazolidinedione is added to an existing
combination of metformin and glyburide.[24]
All
thiazolidinediones cause weight gain. This weight gain is partially due to
fluid retention. An increase in plasma volume results in a small drop of about
1% in hematocrit. In some susceptible patients, fluid retention may trigger
congestive heart failure. This phenomenon occurs far more frequently in
insulin-treated patients receiving a thiazolidinedione. There is also increased
adiposity, although some studies suggest relative sparing of visceral fat. All
thiazolidinediones cause a slight increase in low-density lipoprotein (LDL)
levels and a substantial increase in high-density lipoprotein (HDL) levels.
Thus, the LDL-to-HDL ratio actually decreases. There is also a slight lowering
of blood pressure. As single-use agents, the thiazolidinediones do not cause
hypoglycemia. They are entirely safe in patients with renal impairment. Animal
studies suggest an increase in heart size in thiazolidinedione-treated animals.
Careful, long-term echocardiographic studies in troglitazone-, rosiglitazone-,
and pioglitazone-treated patients have shown no adverse cardiac effects.[22]
The most exciting
aspect of thiazolidinedione therapy appears to be the suggestion of a
long-acting effect of these agents. Both sulfonylurea- and metformin-treated
patients experience a gradual loss of efficacy over time, the phenomenon of
so-called "secondary failure." In contrast, thiazolidinedione effects
appear to be maintained over longer periods. The most long-lasting studies have
been carried out with rosiglitazone. Rosiglitazone-treated patients maintain stable
HbA1c levels for over 2 years (Figure), whereas glyburide-treated patients,
after first showing rapid improvement, then experience a progressive rise in
HbA1c from initial improved values.
Open in a separate
window
Figure 1
Maintenance of HbA1c
with thiazolidinedione treatment.
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Future Agents
There has been an
influx of new agents in the past several years. Many more are likely to follow
in the near future. The evolving understanding of the PPAR system is leading to
increased drug discovery in this area. The isoxazolidinediones lack the thiol
group but affect the same system. The challenge is clearly to achieve
reductions in insulin resistance without triggering fluid retention and weight
gain.
The goal of achieving
glucose reduction without weight gain is clearly desirable. The disaccharidase
inhibitors and metformin are the principal agents to accomplish this goal.
Efforts are under way to attempt to selectively activate those portions of the
complex of the PPAR system and the retinoic acid dimer that lead to increased
insulin sensitivity and improved lipid metabolism without triggering the
differentiation of adipocytes, which occurs with current-day
thiazolidinediones. PPAR-gamma ligands, which also behave as partial PPAR-alpha
or PPAR-delta agonists, may also be found later to be useful in regulating
dyslipemia as well as glucose levels. Ligand agents known as rexinoids are also
being tested to determine whether they interact with the RXR component of the
PPAR-gamma-RXR heterodimer to modify insulin sensitivity and dyslipemia.
Amylin is a 37 amino
acid polypeptide secreted by the beta cell concurrently with insulin. Amylin
slows gastric emptying and inhibits postprandial glucagon secretion. Amylin
concentrations, like those of insulin, are reduced in type 1 diabetic patients.
The amylin analogue pramlintide has been developed as an injectable agent for
treatment. Although the reduction of HgbA1c by pramlintide is modest, there
have been reductions in weight in both type 1 and type 2 diabetic patients
taking this agent.[25]
Beta-3 agonists are
under study as antidiabetic agents. Their effect appears to be mediated by
enhanced thermogenesis and increased glucose uptake.[26] It is hoped that these
agents may reduce glucose levels while decreasing adiposity.[27]
Glucagon-like peptide
1 (GLP-1) is a hormone secreted by the intestines during food absorption. It
has multiple effects, including the stimulation of insulin release, the
suppression of glucagon release, and a reduction in appetite.[28] GLP-1 is
rapidly degraded in the circulation by dipeptidyl peptidase IV. Various
analogues of GLP-1 have been developed that are relatively resistant to
degradation. One agent, exenatide, has shown promise in reducing glucose levels
and weight in type 2 diabetic patients and is in active development.[29] GLP-1
and its analogues must be administered by injection. The alternative approach
is to inhibit dipeptidyl peptidase IV to conserve endogenous GLP-1. Several
agents are under study and have the benefit of oral administration rather than
injection.[30]
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Changes in Drug
Management of Type 2 Diabetes
For many years, there
were few pharmaceutical options for the treatment of type 2 diabetes. Now, new
sulfonylureas, metformin, the disaccharidase inhibitors, the
thiazolidinediones, and meglitinides have rapidly become available. It is hoped
that the new agents will lead to improved diabetic control and a lower
incidence of diabetic complications, and, ultimately, to lower mortality. The
Diabetes Control and Complications Trial in the United States and the Swedish
Diabetes Intervention Study have pointed to a reduction of microvascular
disease in type 1 diabetes with an improvement in glycemic control.[31,32] However,
the majority of diabetic patients have type 2 diabetes. Large-vessel disease
affecting the coronary, cerebral, and peripheral arteries is a much more
significant source of morbidity and mortality in this older population than
microvascular disease.[33] Although improved glycemic control is associated
with a reduced risk of coronary artery disease, concurrent improvement also
occurs in the associated factors of obesity, hypertension, and dyslipidemia. It
is not entirely clear how much of the reduction in cardiovascular risk is due
to better glucose levels as opposed to the concurrent improvement in the
associated risk factors.[34,35]
The results of the
United Kingdom Prospective Diabetes Study (UKPDS) have shed some light on these
issues.[36,37] This study, which began in 1977, was much larger than the old
UGDP study with over 4000 patients at 23 centers randomized to either diet
therapy alone or pharmacologic therapy with either sulfonylurea, insulin, or
metformin. Only obese patients were treated with metformin. There was an effort
to isolate the additional effect of hypertension in their population by the
addition of either captopril or atenolol in a substudy. The study concluded in
1997, after a median duration of randomized treatment of 11 years (6-20 years).
After 9 years, the difference in HbA1c between the conventional and the
intensively treated groups was 0.9%, with no differences between the insulin,
sulfonylurea, and metformin groups. In the pharmacologically treated groups,
there was a 25% risk reduction for microvascular end points, which included
retinal disease and renal disease. The benefit of pharmacologic therapy on the
macrovascular end points was much smaller. There were no significant
differences between the groups in the risk of fatal myocardial infarction,
heart failure, angina, stroke, amputation, or death from peripheral vascular
disease. There was a significant risk reduction in episodes of sudden death and
a borderline difference in the incidence of nonfatal myocardial infarction
favoring pharmacologic therapy. In contrast, the results of the substudy of
antihypertensive treatment were far more impressive. There was a 32% reduction
in diabetes-related mortality, a 44% reduction in stroke, and a 37% reduction
in microvascular disease.
The most important
result of the UKPDS was to show the equivalence of sulfonylureas, metformin,
and insulin therapy in the end points of the study, including diabetic
complications and overall mortality. Thus, the findings of the UGDP study were
not duplicated. However, the complexity of the study design has led to much
controversy over the interpretation of the results. In particular, metformin
therapy showed a clear superiority in outcomes over sulfonylureas and insulin
in obese patients. However, patients in whom metformin was added to
sulfonylurea treatment in an attempt to improve glycemic control actually
showed higher mortality than if sulfonylureas were simply maintained. These
contradictory findings leave some uncertainty in the interpretation of the
results. One of the major lessons of the UKPDS was to demonstrate that
treatment of non-insulin-dependent diabetes with a single agent is not
sufficient to attain the target goal of normalization of HbA1c. Patients in the
UKPDS started at an HbA1c level of about 7%. Although the level of attained
benefit in the pharmacologically treated group as compared with the
diet-treated group was 0.9%, there was still a deterioration over 10 years to
7.9%, with no advantage for any one pharmacologic group.[38] Clearly, these
levels are far from the target of normal HbA1c.
No one drug is
capable of normalizing HbA1c in the vast majority of patients. This is
particularly true in view of the progressive deterioration in control
demonstrated in monotherapy in the UKPDS. However, each class of drugs shows
additive benefits when added to other classes. Fortunately, metformin and the
thiazolidinediones each reduce insulin resistance by different synergistic
mechanisms. The combination of metformin and rosiglitazone has shown particular
strength in combined treatment. The addition of sulfonylurea adds increased
insulin secretion to the benefits of decreased insulin resistance. There is now
increasing usage of multiple drugs in the treatment of type 2 diabetes. This
change in physician perspective is due to acceptance in the medical community
of the belief that even limited abnormalities of serum glucose are harmful. The
UKPDS demonstrated a definite advantage of pharmaceutical management. In
addition, many of the new drugs offer less risk of hypoglycemia than the
sulfonylureas. Metformin, disaccharidase inhibitors, and thiazolidinediones do
not provoke hypoglycemia unless coupled with the use of sulfonylureas or
insulin. The new insulin secretagogues have a lower incidence of hypoglycemia
because their action is mainly during and shortly after a meal.
The use of 3 or more
drugs in combination is even now becoming commonplace. Oral hypoglycemics have
always offered a needleless alternative to insulin therapy. Thus, patients have
accepted regimens with multiple oral agents as a refuge from insulin treatment.
However, it is very useful to support the effects of oral insulin sensitizers,
such as metformin and the thiazolidinediones, with an augmentation of serum
insulin levels. In this respect, sulfonylureas can only achieve limited
improvement in endogenous insulin secretion.
There are 2
developments that may help increase the acceptability of insulin treatment. One
is the development of glargine insulin. This synthetic insulin achieves very
stable baseline insulin levels over a 24-hour period. Thus, a once-daily
injection may suffice to augment insulin levels to a range in which insulin
sensitizers can then achieve normoglycemia.[39] The second promised change in insulin
treatment is inhaled insulin. The extensive lung surface permits a significant
absorption of insulin. Several studies have now shown that inhalation of
insulin before a meal can reduce glucose excursions as much as does injected
insulin. Type 1 diabetic patients still require injections to provide a basal
insulin level, which is then augmented by inhaled insulin. However, type 2
diabetic patients typically have significant basal insulin secretion. The use
of inhaled insulin at meals could provide the necessary boost to allow insulin
sensitizers, such as metformin and the thiazolidinediones, to maintain glucose
control. If inhaled insulin does not show long-term deterioration of lung
function, then the combination of inhaled insulin with insulin sensitizers will
have a significant impact on glucose control.
Diabetes is one of
the most common health problems, particularly of the aging population. Although
its eradication is not likely with the use of drugs, we anticipate that
multiple drug regimens will lead to improved glucose control in the diabetic
population. It is expected that the new regimens will permit normal HbA1c
levels to be achieved in most if not all patients. It is hoped that
normalization of glycemic levels will then lead to a marked reduction in the
diabetic complications that have afflicted so many people.
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Footnotes
The author received a
grant from the Association of Diabetes Investigators to support the preparation
of this manuscript. This grant was partially funded supported by unrestricted
educational grants from Aventis, GlaxoSmithKline, Novartis, Takeda, and
Sanofi-Synthelabo.
This program was
supported by an independent educational grant from Pfizer, Inc.
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