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Recent
Clinical Developments in Type 2 Diabetes
Preventing
Diabetes and Preventing Cardiovascular Events in Diabetics
By
Allan
B. Haberman, Ph.D.
Haberman
Associates, The Biopharmaceutical Consortium
October 19, 2006
The
market for a diabetes-prevention drug is potentially $15
billion per year, according to a recent report in The
Wall Street Journal. There are an estimated
54 million people in the
US
with prediabetes, the American Diabetes Association says.
Prescribing an approved antidiabetic drug to prediabetic
individuals is thus an option being examined for the
prevention of diabetes and its corollaries.
In this
Strategic Briefing, we report on the results of recent
trials that studied the ability of marketed antidiabetic
drugs to 1) prevent diabetes, and 2) prevent
cardiovascular (CV) events in those patients already
diagnosed. The decision to prescribe an antidiabetic drug
to a prediabetic individual must take into account the
differential between successful reduction in progression
to full-blown diabetes, and the adverse side effects of
some antidiabetic drugs. The chasm is further widened when
one considers the proven efficacy and safety that
intensive lifestyle modifications related to diet and
exercise can have on reducing disease incidence.
Nevertheless, the following paragraphs highlight the
urgent need to curb the ever-increasing incidence of
diabetes—whether by using drugs or via lifestyle
interventions.
Diabetes
is a public health crisis…
Development of new means of prevention of diabetes, and of
prevention of CV events in diabetics, is critical for the
United States
, and for much of the world. The
latest WHO (World Health Organization) estimate for the
number of people with diabetes, worldwide, in 2000, was
177 million. By 2025 WHO predicts that number will
increase to at least 300 million people.
In 2005,
5.62% of Americans had been diagnosed with diabetes. The
Centers for Disease Control and Prevention (CDC) predicts
the prevalence of diabetes will double by 2050, driven by
the alarming rise in obesity in the
United States
. Obesity carries with it a decidedly higher risk of
developing diabetes. At the same time, this increase in
obesity is also occurring in much of the rest of the
world, especially in
India
and
China
. Diabetes itself greatly increases the risk of CV disease
(CVD), which is the major cause of death in type 2
diabetics.
…and
it poses an economic burden. According
to the American Diabetes Association, the total annual
economic cost of diabetes in 2002 was estimated at $132
billion, or one out of every 10 health care dollars spent
in the
United States
.
The market for oral
antidiabetic drugs is lucrative. According to one recent
report, in
2004 the global diabetes drugs treatment market reached a
value of over $13 billion. Of this value, oral
antidiabetics took a 54% market share and had a growth
rate of 9% (Visiongain, “The World Diabetes Market,
2005–2011,” March 2006). Clearly, companies with
marketed antidiabetic drugs would like to expand their
labels to include preventive use.
At last
month’s 42nd Meeting of the European
Association for the Study of Diabetes (EASD) (Copenhagen,
Denmark and Malmo, Sweden; September 14–17, 2006),
several presentations were made on prevention of type 2
diabetes and prevention of CV complications in type 2
diabetics. These presentations were based on current
results from two large, double-blind randomized
placebo-controlled clinical trials: DREAM (Diabetes
Reduction Assessment with Ramipril and Rosiglitazone) and
PROactive (PROspective PioglitAzone Clinical Trial in
MacroVascular Events). Most of the results of these
clinical trials were also published in leading medical
journals (see reference list at end of article).
DREAM was
designed to study prevention of progression to diabetes in
prediabetic individuals by administration of either
ramipril (Sanofi-Aventis/Wyeth/King Pharmaceuticals’
Altace) or rosiglitazone (GlaxoSmithKline’s Avandia).
PROactive was designed to study prevention of CV events in
type 2 diabetics who already had macrovascular disease by
administration of pioglitazone (Lilly/Takeda’s Actos).
Information on these drugs and the goals of these trials
are summarized in Table 1.
For
companies that are the developers of drugs tested in these
trials, definitive success in preventing diabetes in
prediabetics or CVD in diabetics may result in a major
expansion of the market for their drugs. As it stands,
pioglitazone and rosiglitazone achieved combined 2004
global sales of US $3.96 billion shared between Takeda and
Eli Lilly (52%) and GlaxoSmithKline (48%), according to La
Merie Business Intelligence. In 2005, Avandia achieved
worldwide sales of $2.45 billion.
Table 1: Drugs tested
in the DREAM and PROactive trials
|
Drug
|
Drug
Class
|
Approved
indications
|
Potential
new indication tested in DREAM or PROactive trial
|
|
Ramipril
(Sanofi-Aventis/Wyeth/King
Pharmaceuticals’ Altace)
|
ACE
inhibitor
|
Hypertension;
prevention of CV events in patients over 55 with a
high risk of developing a major CV event.
|
Prevention
of diabetes in prediabetic individuals.
(DREAM)
|
|
Rosiglitazone
(GlaxoSmithKline’s Avandia)
|
PPARg
agonist (insulin sensitizer)
|
To
improve glycemic control in type 2 diabetics, either
as a monotherapy or in combination with other
standard antidiabetic agents, and together with diet
and exercise.
|
Prevention
of diabetes in prediabetic individuals.
(DREAM)
|
|
Pioglitazone
(Lilly/Takeda’s
Actos)
|
PPARg
agonist (insulin sensitizer)
|
To
improve glycemic control in type 2 diabetics, either
as a monotherapy or in combination with other
standard antidiabetic agents, and together with diet
and exercise.
|
Secondary
prevention of CV events in type 2 diabetics with
macrovascular disease.
(PROactive)
|
Source:
Haberman Associates
Background:
Preventing
progression to type 2 diabetes in prediabetic individuals
by diet/exercise or metformin.
The
metabolic syndrome, which is present in large numbers of
people in the
United States
and increasingly in the rest of the world, is a risk
factor for development of type 2 diabetes, as well as for
CVD. The metabolic syndrome is a cluster of risk factors
that include abdominal obesity, dyslipidemia,
hypertension, insulin resistance (with or without impaired
glucose tolerance), and elevated fasting blood glucose.
People with three or more of these risk factors are deemed
to have the metabolic syndrome. Those with abnormalities
in glucose levels are considered to be prediabetic.
Specifically,
those with fasting blood glucose levels between 100
milligrams per deciliter (mg/dL) and 126 mg/dL are
considered to have elevated fasting blood glucose and to
be prediabetic; those with levels over 126 mg/dL are
diagnosed with diabetes. Individuals with impaired glucose
tolerance (140–199 mg/dL after a 75-gram oral glucose
challenge) are also prediabetic. Approximately one-third
of prediabetics progress to diabetes.
Current
treatment for prediabetics consists of recommendations for
diet, exercise, and weight loss from their primary care
physicians. Results of a study by the Diabetes Prevention
Program (DPP) showed that a more intensive program of
diet/exercise intervention can be effective in preventing
diabetes over the short term, as can treatment with the
well-established oral antidiabetic metformin (Merck KgaA/Bristol-Myers
Squibb’s Glucophage; also available in generic form). In
this large randomized trial in 3,234 prediabetic subjects
over a mean period of 2.8 years, an intensive program of
lifestyle intervention (diet, exercise, and weight-loss
recommendations, including individualized one-on-one
instruction over a 24-week period) reduced the incidence
of diabetes by 58%; metformin treatment reduced the
incidence of diabetes by 31% as compared with placebo (DPP
Research Group 2002). Thus, a more intensive version of
the lifestyle modification that is the mainstay of current
treatment of prediabetics proved significantly more
effective than metformin over the short term.
Because
of the significant benefit of both interventions in the
DPP, the trial was terminated prematurely. This prevented
the trial from assessing the long-term effects of
intensive diet/exercise interventions and metformin.
However, a long-term outcomes study (over a five-year
period) of participants in the trial has been in progress,
with the results not yet determined (Ratner; The Diabetes
Prevention Program Research Group 2006).
Nevertheless, unpublished results of a smaller clinical
trial in Finland indicate that the benefits of intensive
lifestyle intervention in preventing diabetes are
sustained for many years (Tuomilehto and Wareham 2006;
Tuomilehto, Lindstrom, Erickson et al. 2001).
Most
prediabetic individuals do not receive intensive lifestyle
intervention, which is usually difficult to administer in
the primary care setting, and is often difficult for many
patients to fit into their schedules. Especially under
these “field conditions,” long-term maintenance of
weight loss sufficient to reduce the risk of developing
diabetes (5–10% of body weight) is difficult for most
overweight or obese people, including prediabetics.
[However, the Finnish study indicates that meeting the
exercise goals of an intensive lifestyle intervention
program significantly reduces the risk of developing
diabetes even in prediabetic individuals who do not meet
the weight-loss goals of the program (Tuomilehto,
Lindstrom, Erickson et al. 2001).] Because of this,
researchers are interested in developing other means to
prevent diabetes in this population. The DREAM trial
represents studies aimed at determining whether ramipril
or rosiglitazone treatment may constitute such preventive
therapies.
Can
ramipril prevent progression to type 2 diabetes in
prediabetic individuals?
The DREAM
trial consisted of two arms: one comparing ramipril and
placebo, and the other rosiglitazone and placebo. Ramipril
is an angiotensin-converting enzyme inhibitor (ACEI)
approved for the treatment of hypertension and for
prevention of CV events in patients older than 55 with a
high risk of developing a major CV event. Rosiglitazone is
an oral antidiabetic agent. It is an insulin sensitizer of
the thaizaolidinedione (TZD) class of drugs. Studies with
the other marketed TZD, pioglitazone, are discussed later
in this article. TZDs are peroxisome proliferator-activated
receptor (PPAR) agonists that target PPARg,
which controls glucose metabolism and adipocyte
differentiation.
The
results of the rampiril arm were simultaneously reported
at the EASD meeting and published in the online edition of
the New England
Journal of Medicine (The DREAM Team Investigators
2006). In this arm of the trial, 5,269 prediabetic
patients (without CVD, uncontrolled hypertension, or heart
failure, and with fasting blood glucose between 110-126
mg/dL or blood glucose between 140–200 mg/dL in an oral
glucose tolerance test) were randomized to receive
ramipril or placebo. The patients were followed for a
median of three years. The primary outcome was the
incidence of diabetes or death, and secondary outcomes
included regression to normoglycemia. There was no
significant difference between the ramipril group (18.1%)
and the placebo group (19.5%) in the incidence of the
primary outcome. Among the secondary outcomes, at the end
of the study 42.5% of subjects in the ramipril group had
fasting blood glucose levels below 110 mg/dL and normal
glucose tolerance tests, as compared to 38.2% of subjects
in the placebo group. This difference was statistically
significant.
Based on
these results, the researchers concluded that ramipril was
ineffective in preventing diabetes in this population over
the study period, but that it had a modest positive effect
on glucose metabolism. The difference between the ramipril
group and the placebo group in the primary outcome
diverged during the third year, however, with the rampiril
groups showing a lower incidence. This suggests the
possibility that a longer follow-up period might have
shown a significant benefit of ramipril in the prevention
of diabetes.
The
results of the ramipril arm of the DREAM study appear to
contradict the results of earlier studies that suggested
that ramipril might have a positive effect in preventing
diabetes in some populations.
These trials were not, however, specifically
designed to determine whether ramipril prevents diabetes.
Moreover, subjects in these earlier studies had
uncontrolled hypertension, CVD, and/or heart failure, and
were older by an average of 10 years than participants in
the DREAM study. Therefore, it is possible that ramipril
may be beneficial in preventing diabetes in these other
populations. For example, in the Heart Outcomes Prevention
Evaluation (HOPE) trial, researchers showed that patients
older than 55 with vascular disease or diabetes plus one
other CVD risk factor, but without heart failure, who were
treated with ramipril were 34% less likely than
placebo-treated patients to report a new diagnosis of
diabetes over the mean five-year period of the trial (The
HOPE Investigators 2000).
Despite
the lack of evidence for the efficacy of ramipril in
preventing diabetes in the DREAM study, ramipril or other
ACEIs may still represent good choices in treating
hypertension and/or various other conditions in
populations of patients with metabolic syndrome, impaired
fasting glucose or glucose tolerance, or diabetes. For
example, in the HOPE trial rampiril significantly reduced
the rate of death from CV causes, myocardial infarction
(MI), and stroke (as compared to placebo) in the patients
at high risk for CVD (most of whom had diabetes or
metabolic syndrome) who were the subjects in this trial.
Moreover, among commonly prescribed classes of
antihypertensives, thaizide diuretics and beta-blockers
may exacerbate the metabolic syndrome and increase the
risk of developing diabetes (Taylor, Hu, and Curhan 2006).
Therefore, other classes of antihypertensives, including
ACEIs and calcium-channel blockers (both of which include
drugs available as generics), may be better choices for
many patients with hypertension and other aspects of the
metabolic syndrome.
Can
rosiglitazone prevent progression to type 2 diabetes in
prediabetic individuals?
The
methodology, types of patients studied, and clinical
endpoints for the rosiglitazone arm of the DREAM trial
were the same as for the ramipril arm. 5,269 patients were
randomized to receive either rosiglitazone or placebo, and
followed for a median of three years. The results of the
trial were presented at the EASD meeting, and
simultaneously published in The
Lancet (DREAM Trial Investigators; Gerstein HC, Yusuf
S, Bosch J, et al. 2006). In this study, 11.6% of subjects
treated with rosiglitazone and 26.0% of subjects treated
with placebo developed the composite primary outcome
(diabetes or death). Rosiglitazone gave a statistically
significant reduction in the risk of developing the
primary outcome of 60%, and a 62% reduction in the risk of
developing diabetes as compared to placebo.
Because
of the three-year duration of the DREAM trial, the results
of longer-term treatment with rosiglitazone, or whether
the results seen with rosiglitazone persist after
termination of treatment, remain unknown. The DREAM
investigators plan to present the results of such
“washout data” (i.e., results after termination of
treatment) at a later meeting. As a note, the results with
earlier studies with the TZD troglitazone
(Warner-Lambert’s Rezulin, which was discontinued for
safety reasons) suggested that the risk of diabetes
returned to untreated levels after termination of drug
treatment.
The DREAM
study showed that rosiglitazone is effective in reducing
the risk of diabetes in prediabetic individuals over the
short term. Despite this, the long-term effects of
treating prediabetic individuals with rosiglitazone, both
in terms of efficacy and safety, are unknown. As discussed
in a previous Pharma
DD article, TZD treatment is associated with weight
gain, and more rarely peripheral edema and congestive
heart failure (CHF) (Haberman 2006). The DREAM
investigators did report significant weight gain in
rosiglitazone-treated patients in their study, as well as
a significant sevenfold increase in the incidence of heart
failure (0.5% of rosiglitazone-treated patients, as
compared to 0.1% in the placebo group) over the three-year
period of the trial. Moreover, rosiglitazone treatment
also gave a 37% increase in a composite of CV events (2.9%
of rosiglitazone-treated patients versus 2.1% in the
placebo group), which was not statistically significant.
However, this increase, together with the significant
increase in heart failure, troubled Steven Nissen
(Cleveland Clinic), who was also the lead author of a
safety analysis of the discontinued dual PPAR agonist
muraglitazar (Bristol-Myers Squibb’s Pargluva) discussed
in the earlier Pharma
DD article (Herper and Kang 2006). This is of special
concern to Nissen because otherwise healthy prediabetic
patients such as those studied in the DREAM trial have a
low risk of CV events, and because of the short-term
nature of the trial. It is possible that in longer-term
studies, the risk of CV events would reach statistical
significance.
The
unknown long-term effects of rosiglitazone treatments in
prediabetic patients, as well as the high cost of
treatment and the increased risk of heart failure, may
well limit third-party payers’ willingness to fund
treatment in this population. Moreover, intensive
lifestyle intervention gives comparable results to
rosiglitazone, without the adverse effects of the drugs
and with the potential for long-term benefits (Tuomilehto
and Wareham 2006). As discussed earlier, however, the
great majority of patients do not receive intensive
lifestyle interventions. Moreover, otherwise healthy
prediabetic patients are treated by primary care
physicians, who are likely to be hesitant to prescribe
rosiglitazone for these patients because of the same
factors, and who tend to be conservative about prescribing
novel treatments before they are well proven.
Factors that militate against the use of
rosiglitazone in diabetes prevention, despite the results
of the DREAM trial, are summarized in Table 2.
Table
2: Factors that militate against the use of rosiglitazone
in prevention of diabetes in prediabetic individuals
- Risk
reduction with rosiglitazone is comparable to that
with intensive lifestyle (diet and exercise)
intervention, a safe, cost-effective, and proven
alternative
- Rosiglitazone
treatment is associated with weight gain, which
counters the central role of weight loss in treatment
of metabolic syndrome
- Lack
of data on long-term efficacy and safety of treatment
Source: Haberman
Associates
Can
pioglitazone prevent CV events in type 2 diabetics?
The
results of the PROactive study on the effects of
pioglitazone treatment in secondary prevention of CV
events in type 2 diabetics with macrovascular disease were
presented at the September 2005 EASD meeting (Athens,
Greece), and a month later published in The
Lancet (Dormandy, Charbonnel, Eckland, et al. 2005).
Updates on this study were presented at the 2006 EASD
meeting.
PROactive
was a double-blind randomized placebo-controlled study in
5,238 patients with type 2 diabetes and evidence of
macrovascular disease (e.g., previous MI, stroke, coronary
revascularization, or peripheral arterial disease, etc.).
These patients were randomized to receive either
pioglitazone or placebo; they were concurrently treated
with standard medications for type 2 diabetes,
dyslipidemia, hypertension, and with antiplatelet drugs
such as aspirin. Mean follow-up was 2.8 years.
The investigators found a nonsignificant 10%
reduction by pioglitazone as compared to placebo in the
study’s primary endpoint (a composite of all-cause
mortality, nonfatal MI, stroke, major leg amputation,
acute coronary syndrome, and cardiac or leg
revascularization). They also found a significant 16%
reduction by pioglitazone as compared to placebo in the
prespecified secondary endpoint (all-cause mortality,
nonfatal MI, and stroke). The investigators concluded that
the results with the primary endpoint were influenced by
the lack of effect of pioglitazone treatment on cardiac
and leg revascularization. This might be because the
decision to perform these procedures is influenced by
local medical practice.
In terms
of safety, there was a significant increase in reported
cases of heart failure with pioglitazone as compared to
placebo (11% versus 8%), as well as pioglitazone-related
weight gain and edema. Heart failure was not a centrally
adjudicated event in this trial, however, and reports of
heart failure may have been affected by the increased
cases of edema (a symptom of heart failure) owing to the
drug treatment. Patients are nevertheless faced with a
trade-off between increased vascular health and the
potential for heart failure. Weight gain is also a factor
that runs counter to weight-reduction goals for the
treatment of diabetes and CVD.
The
update to the PROactive study presented at the 2006 EASD
meeting was a prespecified subgroup analysis of the
previously published trial results. In this analysis, the
researchers found that pioglitazone treatment reduced the
recurrence of stroke in patients who had a prior history
of stroke by a statistically significant 47% as compared
to placebo. There was no significant reduction in the rate
of new cases of stroke in patients who had no prior
history of stroke, however.
Despite
the positive findings of the PROactive trial, it is not
likely to change medical practice because of questions
about the tradeoff between CV benefits of pioglitazone
versus its adverse effects. Pioglitazone (and
rosiglitazone) are important components of the
armamentarium of oral agents to treat the hyperglycemia
associated with diabetes, as well as other components of
the metabolic syndrome seen in type 2 diabetics.
However, it is not likely that physicians will want
to prescribe pioglitazone specifically to prevent CV
events in type 2 diabetics who are not already receiving
the drug.
Outlook
As
discussed previously, it is unlikely that the results of
either the DREAM or PROactive trials will change medical
practice, or result in market expansions for any of the
drugs tested in the trials. The trade-off between the
adverse effects of TZDs and their benefits as demonstrated
in the trials is a major factor that militates against
their expanded use. In the case of prevention of diabetes
in prediabetic individuals, this has led some industry
commentators to propose that other non-TZD oral
antidiabetics be tested for diabetes prevention in this
population. In particular, two novel late-stage drugs that
work via a mechanism different from TZDs and other current
drugs, sitagliptin (Merck’s
Januvia, approved by the FDA in October 2006) and
vildagliptin (Novartis’ Galvus, which may be approved
before the end of 2006), have been suggested as candidates
(Herper and Kang 2006).
However, although the approval of sitagliptin opens the
door to clinical trials on diabetes prevention, any
results are speculative and are years away. Therefore,
intensive lifestyle intervention remains the best therapy
for diabetes prevention in prediabetic individuals.
Allan
B. Haberman, Ph.D. is Principal of Haberman
Associates,
Wayland, MA.
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Copyright 2006, All Rights Reserved. Cambridge
Healthtech Institute.
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