By Melanie Fridl Ross
GAINESVILLE, Fla. - Aggressively lowering high blood pressure with a treatment strategy that includes a calcium antagonist not only decreases the risk of heart attack, stroke or death - in a surprising twist, it also appears to slash the chance high-risk patients will develop diabetes, University of Florida researchers reported today (12/2) in the Journal of the American Medical Association.
Scientists involved in the landmark International Verapamil SR-Trandolapril study, known as INVEST, were intrigued by the finding in part because patients with high blood pressure and cardiovascular disease are much more likely to develop diabetes, and those who do are much more likely to suffer a heart attack or stroke or die. Study participants randomly assigned to receive a sustained-release form of the calcium antagonist verapamil followed by the angiotensin-converting enzyme inhibitor trandolapril were 15 percent less likely to develop diabetes than those who received the beta-blocker atenolol and the diuretic hydrochlorothiazide, said the study's principal investigator Carl J. Pepine, M.D., a professor and chief of cardiovascular medicine at UF's College of Medicine.
"All hypertensive patients are at risk for diabetes, butpatients who had diabetes when they entered the trial had almost a twofold risk in the primary outcome, which was death, heart attack or stroke," said Pepine, also the current president of the American College of Cardiology. "What that means is once a patient with hypertension and coronary disease has those problems, and then they develop diabetes, it imparts double the risk of having those events. Patients who develop diabetes are very important because it immediately takes them into a very high-risk group."
UF researchers said if the findings, still considered preliminary, can be confirmed by another study, one or two out of every100 hypertensive heart disease patients treated with a verapamil SR-trandolapril strategy for at least three years could avoid diabetes - an advance that would affect thousands. It's not yet clear whether the approach protected against the emergence of diabetes in high-risk patients, or whether the other strategy actually provoked the disease,
Pepine said.
UF researchers tracked more than 22,500 patients from 14countries for two to five years and found that both approaches controlled high blood pressure exceptionally well, safely lowering it below 140/90 in 72 percent of participants, who were mostly elderly. INVEST was primarily designed to test treatment strategies for lowering blood pressure. But shortly after starting the study, sponsored
by Abbott Laboratories, new information became available on the potential for different blood pressure-lowering medications to prevent or delay the onset of diabetes, Pepine said. Accordingly, researchers started tracking the development of diabetes in participants soon after the study began.
Calcium antagonists decrease the work of the heart's bloodpumping, reduce the pressure of blood flow through the body and improve blood circulation through heart muscle. Since the 1960s, beta-blockers have ranked among the most widely used drugs for the treatment of high blood pressure, but a small percentage of patients can't tolerate them because they develop fatigue or other side effects. The drugs fight the condition by reducing the heart's workload, slowing heart rate and decreasing the force with which the heart muscle contracts. Diuretics lower blood pressure.
Study participants assigned to the verapamil strategy also couldreceive the drug trandolapril and/or a diuretic to achieve the target blood pressure or minimize side effects. Those in the atenolol group also could use trandolapril, an angiotensin-converting enzyme, or ACE inhibitor, if needed. ACE inhibitors block an enzyme in the body that causes blood vessels to narrow. If the blood vessels are relaxed, blood pressure decreases and the heart uses less oxygen to pump blood.
More than 50 million Americans have high blood pressure, according to the American Heart Association. Elevated blood pressure isassociated with up to half of all cases of coronary artery disease, the No. 1 killer of men and women in the United States. Yet surveys have shown that 30 percent or less of the patients in the United States who are known to be hypertensive comply with treatment and even a smaller percentage achieve the targeted blood pressure goal.
According to the Centers for Disease Control and Prevention, heart disease is the leading cause of diabetes-related deaths. About twothirds of deaths that occur among people with diabetes are due to heart disease and stroke. Most have blood pressure greater than or equal to 130/80 mmHg. An estimated 18.2 million Americans, meanwhile, have diabetes.
"Diabetes has reached epidemic proportions in our society,"Pepine said. "We're searching for ways to reduce it and for causes of it. It seems to be one of the potential causes might be some of the
treatments we're using."
Having diabetes is as much a risk factor for subsequent heart disease as having had a prior heart attack, said Rhonda Cooper-DeHoff,Pharm.D., a research assistant professor at UF's College of Medicine. The findings are particularly relevant to blacks and Hispanics, who are at greatly increased risk of diabetes: In 2002, more than 11 percent of blacks and 8 percent of Hispanic-Americans over the age of 20 had the disease, she said.
"In INVEST, being Hispanic was the No. 1 predictor of increased risk of developing diabetes," Cooper-Dehoff said. "We currently haveunder way in-depth analyses of both the Hispanics and the blacks enrolled in INVEST to evaluate control of blood pressure and heart disease outcomes in those populations specifically, as well as the onset of diabetes."
Scientists aren't yet sure why the verapamil strategy loweredthe risk of diabetes, but it may have had something to do with how the medications affect the body's ability to use sugar for fuel, Cooper-Dehoff said. Preventing diabetes would have tremendous public health implications and could greatly cut related health-care costs, she added.
It is well-known, thanks to other studies, that ACE inhibitors may prevent diabetes, said Valentin Fuster, M.D., Ph.D., director of theCardiovascular Institute at Mount Sinai School of Medicine in New York.
"The use in this study of the combination of verapamil SR andtrandolapril, and particularly of trandolapril based on previous studies, supports original data in which an aggressive strategy in treating high blood pressure when diabetes and hypertension are combined is key, because it can significantly decrease the impact of the diabetes on cardiovascular disease," said Fuster, also past president of the American Heart Association.
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Medical scientists reported they have significantly delayed the growth of cancerous
human tumors.
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By Arline Phillips-Han
GAINESVILLE, Fla. - University of Florida medical scientists reported today they have significantly delayed the growth of cancerous human tumors in mice by combining a new drug that thwarts blood vessel formation with another new drug that destroys existing vessels.
Addressing an international cancer research conference inBoston, UF radiation oncologist Dietmar Siemann, Ph.D., said combineduse of two experimental drugs - which rob tumors of their blood supply - was more effective in delaying tumor growth than either of the drugs used alone. The annual meeting is held jointly by the National Cancer Institute, the American Association for Cancer Research and the European Organization for Research and Treatment of Cancer.
Siemann, a professor of radiation oncology with the UF College of Medicine and the UF Shands Cancer Center, said animals with kidney tumors or Kaposi's sarcoma, an aggressive cancer associated with AIDS, responded well to the drugs, with no apparent adverse effects. The therapy involved daily injections of the anti-angiogenesis drug for one week, and once-a-day injections of the vascular targeting agent on the Monday, Wednesday and Friday of that same week. The study involved 35 mice.
The two drugs - an anti-angiogenic drug (ZD6474) that blocks thegrowth of new blood vessels and a vascular targeting agent (ZD6126) that damages and destroys vessels already in place - are now being tested in cancer patients through phase 2 clinical trials, but the combination therapy has thus far been limited to research in laboratory animals.
Siemann said the results of his latest studies in mice harboring human malignant tumors indicate that targeting the vasculature inside tumors may prove to be a valuable addition to the treatment of human cancers. The strongest rationale, he said, is the fact that solid tumors are dependent on blood vessels to supply oxygen and other nutrients and to remove waste products.
"When we used only the anti-angiogenic drug in treating mice with kidney tumors and Kaposi's sarcoma, we achieved tumor growth delaysof 25 and 15 days, and with the sole use of the vascular targeting drug we achieved tumor growth delays of 23 and 25 days," Siemann said. "But when we combined the two drugs in the treatment of mice with the same types of malignancies, we documented tumor growth delays of 55 and 86 days."
Treatment was not begun until the human tumors growing insideeach mouse reached the approximate size of a pea, large enough to be detected by physical examination. "Our findings seem more exciting in light of the fact we achieved these antitumor effects with the use of very nontoxic doses of the two selected drugs, and we were dealing with two forms of human cancer that are stubbornly difficult to treat," said Siemann, whose findings on vascular targeting therapies have been reported in The International Journal of Cancer and in Seminars in Radiation Oncology.
"In our latest study, we found that while some tumor types responded better than others, the antitumor response was always enhancedwhen the two treatments were combined," he added. "In one study, we were delighted to find that three of eight treated mice were free of any indications of cancer a year after treatment, indicating they are cured."
Siemann added that more extensive research is needed to determine whether the beneficial effects observed in mice can beduplicated in human cancer patients. "Targeting the vascular supply of tumors has for a long timebeen considered a potential new weapon in cancer therapy, but efforts to inhibit new blood vessel development or to damage the already established vessels in tumors has not achieved the expected level of success," said Michael Horsman, Ph.D., an associate professor of
experimental clinical oncology at the Aarhus University Hospital in Aarhus, Denmark. "Dr. Siemann's preclinical studies using human tumors have now demonstrated that substantial benefit can be achieved by combining these therapies."
The concept of using anti-angiogenic drugs to interfere with and halt new blood vessel growth was pioneered in animal research by Judah Folkman, M.D., a cancer researcher at Harvard University. The late Juliana Denekamp, Ph.D., D.Sc., of Umea University, Sweden, is credited with developing the concept of using vascular targeting agents that directly damage blood vessels and thereby kill tumor cells by starving them of nutrients. Their findings in animals, which gained nationalattention in 1998, have inspired thousands of follow-up studies.
Siemann said recent findings at UF and elsewhere now suggest strong potential benefits to be derived from further testing of combined anti-angiogenic and vascular targeting drugs, and that, in his view, this drug duo also should be evaluated in combination with conventional chemotherapy and/or radiation therapy for various types of cancer.
He conducted his latest studies with co-investigator Wenyin Shi,M.D., Ph.D., an assistant professor of radiation oncology at UF. Their ongoing research is supported by the National Cancer Institute and AstraZeneca Pharmaceuticals, an international company that produces both the anti-angiogenic and vascular targeting agents.
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