FDA formalizes warning of cardiovascular risks for LHRH agonists

According to a media release from the U.S. Food and Drug Administration (FDA) yesterday, the agency has asked manufacturers of the class of drugs known as luteinizing hormone-releasing hormone (LHRH) or gonadotropin-releasing hormone (GnRH) agonists to include warnings about risk for cardiovascular disease and diabetes in product labeling for these drugs.

The LHRH agonists are extensively used in management of prostate cancer, most commonly in men receiving radiation therapy for localized or locally advanced disease and in men with more advanced forms of prostate cancer who have not responded to treatment for localized disease or who have relapsed after such treatment. However, they are also used alone (and perhaps less appropriately) as first-line therapy for some men; in these types of patients,  the relatively benefits of LHRH therapy should be very carefully weighed against the risks for cardiovascular, metabolic, and other complications.

The most commonly used drugs to which this warning will apply are:

  • Leuprolide acetate (Lupron, Eligard, Viadur)
  • Goserelin  acetate (Zoladex)
  • Triptorelin pamoate (Trelstar)
  • Histrelin (Vantas)

This new “class warning” reflects findings from an FDA investigation initiated earlier this year — and discussed on this web site — which showed a relatively small but significant increase in risk for diabetes, heart attack, stroke, and sudden death associated with use of these and similar agents.

3 Responses

  1. Interestingly, the actual FDA report includes the statement: “While our review of these prostate cancer treatments is ongoing and there are some limitations to the data, FDA believes it is important to tell patients and health care professionals that there may be an increased risk of serious side effects,” from Robert Justice, MD, director of the Division of Drug Oncology Products in FDA’s Center for Drug Evaluation and Research. NOTE THE “MAY BE.”

    So, in effect, the jury is still out on how serious this may be. Even the FDA is uncertain, but feels that the labels should at least alert physicians and patients. In fact, physicians are advised, “Patients should not stop treatment with a GnRH agonist unless instructed to do so by a health care professional.”

  2. As always, thanks for bringing this important news to our attention.

    A year ago, even a month ago, I accepted the view that ADT increased the risk of cardiovascular problems. However, I have now read Dr. Mark Scholz’s view of that issue and am not so sure; his view is on page 101 of his new book “Invasion of the Prostate Snatchers.”

    Here’s are key sentences: “Of even greater concern are claims from retrospective studies stating that TIP (testosterone inactivating pharmaceuticals, aka ADT) causes more heart attacks. … The weakness of these retrospective studies is their failure to account for the well-known fact that urologists generally reserve TIP for men who can’t have surgery, those most likely to have pre-existing heart problems. However, there is a single prospective study that also argues for an increased risk of heart attacks with TIP. … Offsetting this are higher quality prospective studies that either show no increased risk … or an actual reduction in the risk of heart attacks. …”

    Thinking about why there appears to be some reduced risk, he notes that women have thinner blood, “creating less trauma to the vasculature.” He notes that testosterone thickens men’s blood, and that TIP reduces that thickness by reducing testosterone, bringing the thickness of men’s blood down into the female range.

    He closes with this thought-provoking statement. “However, the best prospective study evaluating this question shows that the net effect of TIP is an overall reduction in heart attacks by about 10%. The beneficial effect of thinning the blood is apparently sufficient to offset the known increased risks from gaining weight.”

    I’m hoping that the studies Dr. Scholz cites are also prominent in the thinking of the FDA. Maybe that’s why their statement is so tentative, as Chuck indicates.

    My personal, clinical-trial-of-one over nearly 11 years of IADT3 has left me at this point with great cardiovascular numbers and a fasting glucose figure securely in the normal range. I’ve used countermeasures (including simvastatin 20 mg daily) vigorously along with the ADT. (My numbers for September 30, 2010: cholesterol 174, HDL 84, LDL 78, Ratio 2.1, Trigs 60. Fasting glucose was 81 with a reference range of 65-99.) Obviously, one person’s results say nothing about what is likely, but they do prove what is possible.

  3. Dr Scholtz’s hypothesis notwithstanding, the real issue here are the risks associated with the early and arguably unjustifiable over-use of ADT to “manage PSA levels” as opposed to actually treating a patient with curative intent.

    The initial use of current forms of ADT as a replacement for a daily dose of 3 mg of diethystilbestrol (DES) occurred in the early 1980s. Lupron was first approved because — in men with evident and painful metastatic disease (stage D2) — “Suppression of testosterone and dihydrotestosterone and decreases in acid phosphatase were comparable in the two groups. Patients receiving DES experienced more frequent painful gynecomastia (P<0.00001), nausea and vomiting (P = 0.02), edema (P = 0.008), and thromboembolism (P = 0.065) than those receiving leuprolide.” However, the reduction in thromboembolic events in these patients from use of leuprolide as compared to use of DES was not statistically significant.

    Over the years, ADT has been used in a wide variety of patients. In the radiation trials, there appears to have been little difference in the incidence of cardiovascular risk between patients receiving and not receiving ADT. However, there have been no comparable trials of ADT in early stage patients with high levels of comorbidity.

    The idea that ADT would be the treatment of choice for early stage patients who are not candidates for surgery and who already have cardiovascular risk strikes me as naive. These patients are effectively being given palliative therapy (to manage their PSA) which may not be needed (let alone beneficial) until they have evident indication of metastasis. What is more, many of these patients could be treated with radiation therapy if localized treatment is warranted. If localized treatment isn’t warranted, why would one not simply monitor these patients until ADT became necessary? (I suppose just treating them with dutasteride or finasteride is also an option.)

    A PSA of 10 in an elderly man with localized prostate cancer is not normally a clinically significant condition, and the use of any drug that might induce cardiovascular complications in such a patient (especially one who already has cardiovascular problems) would appear to contradict the idea of “first, do no harm.”

    In the real world (as opposed to the world of clinical trials) we are dealing with men who are often not particularly healthy, may well be obese, may have multiple comorbidities, and may have other underlying metabolic issues. Such men are also unlikely to be representative of the highly self-selecting population of patients seen by Dr. Scholtz. They are much more likely to be representative of men in the Medicare and VA databases which were used to track down the additional cardiovascular risk associated with ADT.

    At the end of the day, each patient needs to be managed as an individual, but sometimes the “evidence” from large database studies outweighs that even from clinical trials and the opinions of experts.

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