Cardiology in Review

Volume 11, Number 1, pp. 35–40

Copyright © 2003 Lippincott Williams & Wilkins

Oral Treatments for Type II Diabetes in

Patients with Cardiovascular Disease
RHODA BROSNAN, MD

The incidence of type II diabetes mellitus is rising rapidly, both in the United States and
worldwide. Often, the disease is first diagnosed by cardiologists during an evaluation for
coronary or peripheral vascular disease. It is therefore important to understand the basic
pathophysiology of insulin resistance, its role in the development of type II diabetes, and
its association with accelerated atherosclerosis. An appreciation of when to begin testing
for diabetes, how to make the diagnosis, and what treatment strategy to choose is
imperative. While there are as yet little randomized data to guide hypoglycemic therapy as
it pertains to reducing cardiovascular risk, evidence is accumulating that treatment of
diabetes will have an impact on cardiovascular outcomes.

Key Words: Acute coronary syndromes, Coronary artery disease, Diabetes, Oral hypogly-
cemic.

The incidence of type II diabetes mellitus (DM) is
increasing. It is now estimated to affect over 135
million people worldwide and 14 million people
in the United States (1). Among other conse-
quences, diabetes is associated with the prema-
ture development and accelerated progression of
coronary artery disease (CAD), the clinical impact
of which is startling. Middle-aged patients with
DM but without identified CAD have as high a
risk of myocardial infarction (MI) as nondiabetic
patients with a previous MI (2). Type II diabetes
mellitus in now considered a coronary artery dis-
ease risk equivalent. In addition, diabetes nega-
tively impacts patient outcomes. For example,
after a MI, diabetic patients are more likely than
nondiabetic patients to develop congestive heart
failure (3). Diabetic patients who present with
acute coronary syndromes have almost double the
incidence of reinfarction or death as their nondi-
abetic counterparts (4,5). Given these staggering
statistics, there is a clear and urgent need to un-
derstand better the pathophysiology of type II
diabetes mellitus as it relates to the development
of coronary artery disease and to develop effective
treatment and secondary prevention strategies.
Division of Cardiology, Department of Medicine, Duke University Med-
ical Center, Durham, North Carolina
Address reprint requests to: Rhoda Brosnan, MD, Box 31141, Duke Uni-
versity Medical Center, Durham, NC, 27710.
There is also a need to understand specifically the
relationship of glucose control to clinical out-
comes and how available hypoglycemic treat-
ments may affect this relationship.
DEVELOPMENT AND DIAGNOSIS OF TYPE II DIABETES
Type II diabetes is defined as a chronic disorder
of hyperglycemia that results from a relative defi-
ciency of insulin. The disorder develops in two
stages. The first stage occurs when skeletal mus-
cle, adipose, and hepatic tissue develop resistance
to the actions of insulin. Insulin resistance in
these patients is multifactorial, resulting from
both genetic factors and from acquired predispo-
sitions, most commonly obesity. The initial re-
sponse to insulin resistance is increased insulin
secretion, which is present in the prediabetic
phase. The second stage occurs when hyperinsu-
linemia is no longer able to compensate for the
insulin resistance and frank hyperglycemia devel-
ops. Unless a patient is undergoing routine
screening, the diagnosis of type II diabetes is usu-
ally delayed, occurring well into the process de-
scribed above, when hyperglycemia is finally de-
tected on routine lab work or when the patient has
had overt hyperglycemia long enough to develop
polydipsia, polyuria, or unexplained weight loss.
According to the American Diabetes Association

Volume 11, Number 1, 2003 CARDIOLOGY IN REVIEW 35

(ADA), a normal 8-hour fasting blood glucose
(FBG) is less than 110 mg/dL. A patient with a
FBG between 110 mg/dL and 126 mg/dL has im-
paired glucose tolerance. Type II diabetes is diag-
nosed with a FBG 126 mg/dL or greater on two
separate occasions. The presence of symptoms
combined with a random glucose 200 mg/dL or
greater, confirmed by a FBG of 126 mg/dL or
greater, also establishes the diagnosis. Rarely, an
oral glucose tolerance test can be performed with
a 75-gram anhydrous glucose load when classic
symptoms are present and the FBG is nondiagnos-
tic. The test is positive if the 2-hour postload
glucose is 200 mg/dL or greater (6).
TYPE II DIABETES AND THE DEVELOPMENT OF
CORONARY ARTERY DISEASE
The cut point for diagnosing type II diabetes has
been set at 126 mg/dL because that is the observed
threshold above which microvascular complica-
tions of diabetes such as retinopathy begin to
develop without treatment (6). However, the pro-
pensity to develop CAD begins earlier in the pre-
diabetic phase, when insulin resistance first de-
velops—long before the patient has a diagnosis or
symptoms. Insulin resistance is believed to pre-
dispose to CAD not only because it leads to hy-
perglycemia but also because it is associated with
abnormal lipid profiles characterized by elevated
triglycerides, decreased high-density lipoprotein
(HDL) cholesterol, and increased small, dense
atherogenic low-density lipoprotein (LDL) choles-
terol. It is also associated with increased levels of
clotting factors, including plasminogen activator
inhibitor 1 (PAI-1), fibrinogen, and factor VII, as
well as increased platelet activation and reactiv-
ity. Lastly, insulin resistance results in altered
endothelial and vascular smooth muscle cell
(VSMC) function, contributing to hypertension
and plaque formation. Because type II diabetes is
clinically difficult to diagnose in this early stage
in which an individual is clearly exposed to fac-
tors promoting the development of CAD, the cli-
nician must maintain a high index of suspicion in
patients with factors predisposing to and associ-
ated with diabetes. The ADA recommends that a
FBG be obtained on all individuals aged 45 or
older and repeated at 3-year intervals. Testing
should be considered at a younger age for individ-
uals with predisposing factors such as a positive
family history and those in high-risk ethnic pop-
ulations, including African Americans, Native
36 CARDIOLOGY IN REVIEW
Americans, Pacific Islanders, and Asian Ameri-
cans. Earlier and possibly more frequent testing
should also be performed in patients with any of
the associated factors attributable to insulin resis-
tance, including hypertension, abdominal obe-
sity, hypertriglyceridemia or low HDL, and im-
paired glucose tolerance, the constellation of
which has been termed metabolic syndrome. For
those in whom a predisposition to the develop-
ment of DM has been identified but who do not
yet meet the criteria for the diagnosis, a preven-
tive strategy should be implemented.
Although treatment of the prediabetic stage is
difficult, weight reduction and exercise are key
elements in prevention. A total of 150 minutes of
exercise per week and a weight loss goal of 7%
reduced the incidence of type II diabetes from 11
to 0.8 cases per 100 patient years, according to the
Diabetes Prevention Program (7). Metformin was
also tested and, while not as effective as lifestyle
modification, did significantly reduce the inci-
dence of DM. Other medical therapies that have
been shown to prevent or delay the onset of dia-
betes include the angiotensin-converting enzyme
(ACE) inhibitors captopril (8) and ramipril (9) and
the angiotensin receptor blocker (ARB) losartan
(10). Currently, weight reduction and exercise
should be recommended to all high-risk patients.
ACE inhibitor or ARB therapy should be used in
patients with hypertension and other features of
the metabolic syndrome. Whether to initiate this
treatment in patients without hypertension or to
begin metformin without overt diabetes has not
yet been established.
TREATMENT OF TYPE II DIABETES
Multiple hypoglycemic agents are now avail-
able for the treatment of type II diabetes and can
be divided into two general classes. Insulin-pro-
viding therapies are one class and include the
sulfonylureas, the meglitinides, and insulin itself.
Insulin-providing medicines work as their name
suggests by increasing insulin levels in an attempt
to overwhelm peripheral resistance. Epidemio-
logic data have suggested that the incidence of
macrovascular disease in type II diabetics as mea-
sured by rates of amputation, ischemic heart dis-
ease, death, and stroke is proportional to the de-
gree of hyperglycemia and is generally lower in
groups with excellent glycemic control (HgbA1C
⬍ 7%) compared with groups with poor control
(HgbA1C ⬎ 9%) (11,12). In 1997, a randomized
Oral Treatments for Type II Diabetes
trial of insulin-glucose infusion followed by daily
subcutaneous insulin treatment in diabetic pa-
tients with acute myocardial infarction (DIGAMI
study) was published. A total of 620 patients were
randomized to either the infusion followed by
three subcutaneous injections of insulin for 3
months or usual diabetic care. The patients in the
infusion arm achieved statistically significantly
lower blood glucoses during the infusion and,
after thrice daily injections of insulin for 3
months, had a statistically significantly lower he-
moglobin A1C. The results showed no significant
in-hospital or 30-day mortality benefit in the treat-
ment arm. There was a statistically significant
decrease in mortality at 1 year after randomization
that was questionably related to the short-term
effect of the infusion peri-infarct or the long-term
effect of better glucose control (13). This study
was followed by the largest randomized trial to
date to assess macrovascular outcomes in diabet-
ics, the United Kingdom Prospective Diabetes
Study (UKPDS) 33. A total of 3867 newly diag-
nosed type II diabetic patients were randomized
to intensive hypoglycemic therapy (initially with
insulin or a sulfonylurea) or to conventional treat-
ment, initially with diet alone (14). As shown in
Figure 1, the UKPDS investigators surprisingly
found that intensive sulfonylurea therapy, insulin
therapy, or both did not significantly decrease the
Volume 11, Number 1, 2003
incidence of macrovascular outcomes (MI, stroke,
or rate of amputation) when compared with con-
ventional treatment, despite the maintenance of
significantly lower glycosylated hemoglobins and
fasting blood glucoses in the intensive treatment
group over 10 years of follow-up. This study sug-
gests that simply providing more insulin does
little to prevent the macrovascular complications
associated with type II diabetes.
The second class of pharmacologic agents avail-
able to treat type II diabetes is the insulin-sensi-
tizing medicines. This class includes the bigua-
nide, metformin, and the thiazolidinediones
(TZDs), rosiglitazone and pioglitazone. Insulin-
sensitizing medications do not work in the ab-
sence of insulin. They enhance the actions of
insulin on peripheral tissues; insulin secretion
remains the same or decreases in patients taking
these agents.
Biguanides
Metformin was introduced in 1950 and became
available in the United States in 1995. Its glucose-
lowering effects are secondary to its potentiation
of insulin’s effects on the liver, specifically a de-
crease in gluconeogenesis. The exact mechanism
of metformin action is unclear. In newly diag-
nosed diabetic patients, it is as effective as sulfo-
Figure 1. Clinical outcomes
among patients in United
Kingdom Prospective Diabetes
Study 33 randomized to
intensive sulfonylurea therapy,
insulin therapy, or both (black
bars) compared with
conventional therapy (white
bars).
CARDIOLOGY IN REVIEW 37
nylureas in lowering fasting blood glucose and
glycosylated hemoglobin (15). Additionally, it has
been shown to improve lipid profiles by lowering
total cholesterol, LDL, and triglycerides as well as
by increasing HDL. Further, PAI-1 has been
shown to decrease in patients receiving met-
formin (16). Lastly, patients tend to lose an aver-
age of 8 pounds in the first 6 months of treatment
(17).
Despite these potentially beneficial actions, use
of metformin has been limited because of the fear
of the rare side effect of lactic acidosis. However,
the incidence of lactic acidosis is less than 0.3/
1000 patient years as long as the medication is
avoided in those with a creatinine of greater than
1.5 mg/dL, those with documented liver disease,
and those with congestive heart failure requiring
medical treatment. Metformin should be held the
morning of intravenous contrast exposure and un-
til 48 hours afterward and in the presence of
severe systemic illness to prevent lactic acidosis.
The UKPDS 34 looked at a randomized subset
of intensively treated type II diabetic patients
initially treated with metformin and compared
them with intensively treated patients on sulfo-
nylureas, insulin, or both and those not inten-
sively treated (18). The main results of this
comparison are shown in Figure 2. The met-
formin group had a 7% absolute mortality risk
reduction compared with both other groups and
a statistically significant 7% absolute reduction
in myocardial infarction compared with the
nonintensively treated group, providing a hint
that insulin sensitization may have an impact
on macrovascular outcomes.
38 CARDIOLOGY IN REVIEW
Thiazolidinediones
The thiazolidinediones (TZDs) are newer com-
pounds that work by enhancing insulin effects on
adipose tissue and, to a lesser extent, skeletal
muscle. They work by increasing the transcription
of lipogenic enzymes and glucoregulatory pro-
teins in peripheral tissue via the peroxisome pro-
liferator activated receptor gamma. The resultant
change in adipose and muscle metabolism results
in decreased levels of circulating glucose, im-
provement in lipid profiles, and decreased PAI-1.
TZDs also improve vascular wall function with
reduced endothelial activation, VSMC prolifera-
tion, and inflammation (19,20). In some studies,
the improvement in vascular wall function re-
sulted in decreased diastolic blood pressure and
carotid artery atherosclerotic plaque burden as
measured by B-mode ultrasound (21,22).
There are several side effects associated with
the use of TZDs. First, most patients will have
some weight gain, a result of both plasma expan-
sion and an increase in subcutaneous fat. The
fluid retention is generally insignificant, but be-
cause of it, these medications are contraindicated
in patients with class III or IV heart failure. Be-
cause of the hepatotoxicity associated with trogli-
tazone, the first of the TZDs, which was removed
from the market, the newer TZDs have been care-
fully monitored for this side effect. In preclinical
trials, the incidence of elevated liver function
tests with both pioglitazone and rosiglitazone was
similar to that with placebo (23,24). There have
been only rare postmarketing reports of hepato-
toxicity associated with either medication. Liver
function tests must be monitored every 2 months
Figure 2. Clinical outcomes
among patients in United
Kingdom Prospective Diabetes
Study 34 substudy treated
intensively with metformin alone
(black bars), or treated with
sulfonylureas, insulin, or both
(gray bars), or not intensively
treated (white bars).
Oral Treatments for Type II Diabetes
for the first year of treatment and annually there-
after. There are no randomized data yet to show
that TZDs improve clinical macrovascular out-
comes.
As yet, there are only observational data to sug-
gest that insulin-sensitizing drugs actually prevent
clinically significant atherosclerosis. The Sibrafiban
vs aspirin to Yield Maximum Protection from isch-
emic Heart events postacute cOroNary sYndromes
(SYMPHONY) and 2nd SYMPHONY trials com-
bined randomized approximately 16,000 patients
with ACS to aspirin vs an oral platelet glycoprotein
antagonist, sibrafiban. On review of the 3101 pa-
tients with treated or newly diagnosed diabetes re-
quiring therapy, insulin-providing treatment (which
included insulin, sulfonylurea, or both) was associ-
ated with a higher 90-day combined risk for death,
MI, and severe recurrent ischemia than insulin-sen-
sitizing therapy (which included metformin and,
rarely, a TZD). The odds ratio of 2.5 for the com-
bined outcome persisted after multivariable adjust-
ment (25). Several randomized trials will be looking
at insulin-providing vs insulin-sensitizing strategies
to confirm whether there is a reduction in macro-
vascular events and, importantly, a reduction in
mortality. In the United States, Bypass Angioplasty
Revascularization Investigation 2: Diabetes is one
such study. A total of 2800 patients will be enrolled
and followed over 5 years. One arm of the study will
attempt to show that a target HgbA1C less than 7%
achieved with insulin sensitization results in a
lower 5-year mortality than a similar target achieved
with insulin-providing therapies (26). Whether life-
style modifications alone or combined with these
medications will impact this public health issue by
delaying or preventing diabetes on a large scale also
remains to be determined, as does the impact of
preventing DM on cardiovascular outcomes.
CONCLUSIONS
Type II diabetes is epidemic in the United
States. It is associated with significant cardiovas-
cular morbidity and mortality. To date, random-
ized trials have demonstrated that chronic insu-
lin-providing treatment strategies have no effect
on all-cause mortality or cardiovascular out-
comes. Newer, insulin-sensitizing medications
are as effective in controlling hyperglycemia as
insulin-providing strategies and, when used ap-
propriately, are safe. As yet, there are few data on
whether improving insulin sensitivity will im-
prove cardiovascular outcomes. However, be-
Volume 11, Number 1, 2003
cause of their favorable effects on lipid profiles,
clotting factors, blood pressure, and weight, insu-
lin-sensitizing agents should be considered first-
line therapy in diabetics with cardiovascular dis-
ease. The results of well designed, randomized
clinical trials to determine the efficacy and safety
of these medications in patients with DM are
eagerly awaited.
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Oral Treatments for Type II Diabetes