Insulin sensitizers are poised to become standard medications to reduce the risk of coronary events in patients with Type
2 diabetes, said researchers at the American Heart Association's Scientific Sessions 2005, held recently in Dallas.
In a secondary analysis of PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events), a trial conducted
at 321 medical centers throughout Europe, the insulin-sensitizing agent pioglitazone
(Actos, Takeda) significantly reduced the risk of a second coronary event in patients with Type 2 diabetes.
"This is the first drug in diabetes which has been shown ... to decrease mortality, myocardial infarction [MI]), and acute
coronary syndrome [ACS]," said Erland Erdmann, M.D., lead investigator of the study and a professor of medicine at the University
of Cologne in Germany. "I think it is of utmost importance that this drug lowers cardiovascular risks, especially in those
patients who have the most serious prognosis."
According to Erdmann, pioglitazone attacks multiple cardiovascular risk factors, and its effects include an increase in high-density
lipoprotein cholesterol and decreases in triglycerides, HbA1c values, blood glucose, C-reactive protein, and blood pressure. The improvements in lipid values appear to be unique to pioglitazone
among the insulin sensitizers, he added.
The PROactive study included 2,445 patients with Type 2 diabetes and a previous MI who were randomized to pioglitazone or
placebo in addition to optimal standard therapy with antidiabetic, lipid-modifying, and antihypertensive medications. Fifty-five
percent of the study group were on statin therapy at baseline, which increased to 63% by study's end, said Erdmann.
Patients were followed for a mean of 2.85 years, at which time pioglitazone was associated with a 28% reduction (p = 0.045) in the incidence of a second MI and a 37% reduction (p = 0.035) in occurrence of ACS. There was also a 19% reduction (p = 0.034) in the risk of the cardiac composite endpoint composed of nonfatal MI, coronary revascularization, ACS, and cardiac
death.
It should be noted that the larger PROactive study population included 5,238 high-risk patients. In the larger trial, the
results of which were announced at the 41st annual meeting of the European Association for the Study of Diabetes in Athens,
pioglitazone was associated with a 10% reduction in the primary endpoint of seven different macrovascular events, but it failed
to reach statistical significance (p = 0.095), whereas the combined risk of death, MI, and stroke, a secondary endpoint, was reduced by a significant 16% (p = 0.027) with pioglitazone.
In another study comparing rosiglitazone and metformin in 92 patients with suboptimally controlled Type 2 diabetes, rosiglitazone
(Avandia, GlaxoSmithKline) was associated with a reduction in carotid atherosclerosis of 0.037 mm, as measured by carotid
intima-media thickness (CIMT), whereas CIMT progressed in the metformin group by 0.084 mm; p = 0.02 for the between-group comparison. The difference occurred despite similarly significant improvements in glycemic control,
said Allen J. Taylor, M.D., director of cardiovascular research at Walter Reed Army Medical Center in Washington, D.C.
The fibric acid derivative fenofibrate
(Tricor, Abbott) failed to significantly reduce the incidence of total coronary events in patients with Type 2 diabetes but
significantly reduced the risk of total cardiovascular events, said Anthony Keech, M.D., lead investigator of the FIELD (Fenofibrate
Intervention and Event Lowering in Diabetes) study. FIELD included 9,795 Type 2 diabetes patients who have well-controlled
glucose levels who were treated once daily with micronized fenofibrate, 200 mg, or placebo for five to seven years. None of
the patients enrolled had a clear indication for lipid-modifying therapy, and more than three fourths (78%) had no history
of cardiovascular disease.
Although fenofibrate reduced the risk of total coronary events by 11% compared with placebo, the difference failed to achieve
statistical significance (p = 0.16). Twice as many patients randomized to placebo had statin therapy initiated during the trial. When adjusting for this
difference in drop-in statin use, fenofibrate was associated with a significant 19% reduction in coronary events (p = 0.01), noted Keech, professor of medicine at the University of Sydney, Australia.
Other secondary endpoints favored the use of fenofibrate, including an 11% reduction in total cardiovascular events (p = 0.035), a 21% reduction in coronary revascularization (p = 0.003), and reductions in microvascular endpoints such as progression to albuminuria (p <0.002) and the need for laser treatment for retinopathy (p = 0.0003).
Other studies into cardiac risk included the following:
The antianginal agent ranolazine
(Ranexa, CV Therapeutics), in phase III clinical studies, reduced anginal frequency in patients experiencing three or more
anginal attacks per week despite daily treatment with amlodipine, 10 mg/day, said Peter Stone, M.D., lead investigator of
the Evaluation of Ranolazine In Chronic Angina (ERICA). In the study, 565 patients with angina who were already taking the
maximum labeled dose of amlodipine (10 mg/day) were randomized to ranolazine, 1000 mg twice daily, or placebo. Long-acting
nitrates were permitted, and used by 45% of patients enrolled.
Compared with placebo, ranolazine significantly decreased the mean number of angina episodes per week (p = 0.028), improved the angina frequency component of the Seattle Angina Questionnaire (p = 0.008), and reduced mean weekly nitroglycerin consumption (p = 0.014).
"Ranolazine improves the manifestations of ischemia, such as myocardial stiffness and increased wall tension," said Stone,
codirector of the Samuel A. Levine Cardiac Unit at Brigham & Women's Hospital, Boston. It does so without affecting heart
rate and blood pressure. Previous studies have shown that ranolazine reduces the frequency of angina and increases exercise
duration when used as monotherapy in patients with angina.
Oral anticoagulants remain the treatment of choice for patients with atrial fibrillation (AF). In a trial comparing warfarin
therapy with combination antiplatelet therapy consisting of clopidogrel plus aspirin in 6,500 patients with AF, a difference
in efficacy in favor of warfarin prompted early termination of the study. So reported Stuart J. Connolly, M.D., director of
the division of cardiology at McMaster University in Canada. The annual risk of achieving the primary endpoint of stroke,
MI, embolism, and vascular death was 47% greater (p = 0.0002) in the clopidogrel/ aspirin group compared with the warfarin group. More than three-fourths of the study group
had previous exposure to anticoagulation therapy, which may have biased the study in favor of warfarin, said Connolly.
The Author is a clinical writer based in the Cleveland area.
We subscribe to the HONcode principles of the Health On the Net Foundation