Pharmacology Watch
Erythropoietin and Cancer Death Rates
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In this issue: Does erythropoietin worsen cancer death rates? Most hypothyroid patients can be replaced with levothyroxine alone without additional T3. Does aggressive control in type 2 diabetes save lives?
Erythropoiesis-stimulating agents (ESAs) may increase the risk of death in cancer patients according to a new meta-analysis, which also suggests that the drugs are associated with a significant risk of venous thromboembolism (VTE). Researchers evaluated Phase 3 trials comparing ESAs (erythropoietin and darbepoetin) with placebo or standard care in the treatment of anemia among patients with cancer. The study included 51 trials with 13,611 patients that included survival information, and 38 clinical trials with 8172 patients that included information on VTE. Cancer patients who received ESAs had a higher rate of VTE (7.5% vs 4.9%, RR 1.57 7:95% CI, 1.31-1.87) and increased mortality risks (hazard ratio 1.10: 95% CI, 1.01-1.20). The risk of VTE has been previously reported, but this is the first report that raises the issue of increased mortality associated with use of the drugs. The authors cite eight recent studies which have shown increased rates of tumor progression or mortality with ESA use. These trials raise the concern that the ESAs directly affect tumors, a plausible theory since expression of erythropoietin and erythropoietin receptors has been demonstrated in a variety of human cancers and stimulation of these receptors has been shown to cause tumor effects including proliferation, antiapoptosis, and invasion. The authors conclude that the ESA administration to patients with cancer is associated with increased VTE and mortality risks, and raises concerns about the safety of ESA administration to patients with cancer (JAMA. 2008; 299 (8): 914-924). The FDA has indicated that it will hold a meeting of its Oncologic Drug Advisory Committee in March to review the safety concerns.
Thyroid Replacement Debate Continues
Debate has raged for years whether thyroid replacement with levothyroxine (LT4) provides adequate levels of triiodothyronine (T3) through peripheral conversion, or whether LT4 should be routinely supplemented with T3 in hypothyroid patients. Researchers from Georgetown measured preoperative T3 levels in 50 euthyroid patients undergoing total thyroidectomy. These levels were then compared with postoperative levels T3 while receiving replacement therapy with LT4. There were no significant decreases in T3 concentration in patients receiving LT4 therapy compared with their pre-thyroidectomy T3 levels. Free T4 concentrations were significantly higher in patients treated with LT4 therapy compared with their preoperative T4 levels. Serum TSH levels of 4.5 mIU/L or less were achieved in 94% of patients in the study, however T3 concentrations were significantly lower in the group with TSH levels greater than 4.5. The authors conclude that replacement therapy with levothyroxine (LT4) to achieve TSH levels less than 4.5 results in normal T3 levels through peripheral conversion of T4 to T3, suggesting that T3 administration is not necessary (JAMA. 2008:299:769-777). In an accompanying editorial, David S. Cooper M.D. reminds us that T3 is the active thyroid hormone and has two sources, 20% is produced by the thyroid gland and the other 80% is converted from T4 in peripheral tissues. The peripheral conversion can be affected by starvation, overfeeding, and acute and chronic illness as well as drugs. Multiple studies have shown that replacement with T3 and T4 has no value over replacement with T4 alone. Regardless, many compounding pharmacies continued to prepare long-acting T3 preparations, and such preparations are common in alternative medical practices. Dr. Cooper also notes that several patients in the study cited above did not achieve normal T3 levels with LT4 replacement, and suggests that there is a subset of patients who may benefit from T3 replacement as well. But for the average patient on thyroid replacement this study shows that LT4 replacement alone is adequate (JAMA. 2008; 299:817-819).
Type 2 Diabetes Treatment Okay if Not Too Tight
Tight control of type 2 diabetes is beneficial as long as the control is not too tight. This is the rather confusing message of several recent studies. Aggressive multifactorial intervention in type 2 diabetes including tight glucose regulation, use of renin-angiotensin system blockers, aspirin, and lipid-lowering agents significantly improves mortality according to new study from the New England Journal of Medicine. Researchers in Denmark randomized 160 patients with type 2 diabetes and persistent microalbuminuria to receive either intensive therapy or conventional therapy for a mean of 7.8 years. Patients were subsequently followed for an additional 5.5 years with conventional therapy patients converted to intensive therapy. The primary endpoint at 13.3 years of follow-up was time to death from any cause. The intensive therapy group followed the latest guidelines from the American Diabetes Association, which included hemoglobin A1c target levels of less than 6.5%, a fasting serum total cholesterol level of less than 175 mg/dl, a fasting serum triglyceride level of less than 150 mg/dl, a systolic blood pressure of less than 130 mm Hg, and diastolic blood pressure of less than 80 mm Hg. Patients were treated with renin-angiotensin blockers (ACEI or ARB), and received low-dose aspirin. After 13.3 years, 40 patients in the conventional therapy group died as compared to 24 in the intensive therapy group (hazard ratio[HR} 0.54; 95% CI 0.32-0.89; P= 0.04). Intensive therapy was associate with a lower risk of death from cardiovascular disease (HR 0.43; P=0.04) and of all cardiovascular events (HR 0.4; P <0.001). Six patients in the conventional therapy group ended up with end-stage renal disease compared to one in the intensive therapy group (P=0.04). Fewer patients in the intensive therapy group required retinal photocoagulation as well. The authors conclude that at-risk patients with type 2 diabetes benefit from intensive intervention with multiple drug combinations and behavior modification, and have a sustained benefit with respect to vascular complications and death rates from cardiovascular causes (NEJM. 2008;358:580-591). The study stands in contrast to a recent announcement from the National Heart, Lung, and Blood Institute (NHLBI) that they are halting the aggressive treatment arm of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial because of of a higher mortality rate. The trial enrolled 10,251 at-risk type 2 diabetics who were randomized to medical strategies to intensely lower blood sugar below current recommendations vs less intensive treatment. The aggressive arm targeted hemoglobin A1c levels under 6% while the standard treatment arm had a target between 7% and 7.9%. There were 257 deaths in the intensive treatment group compared with 203 in the standard treatment group over an average of four years of treatment. Extensive analysis has not determined the specific cause for the increased death rate, and no drugs have been specifically implicated including the thiazolidnediones. In Canada, a similar trial (ADVANCE) has enrolled over 11,000 high risk type 2 diabetic patients with a similar design—routine care vs intensive glucose control (A1c <6.5) and risk factor management. ADVANCE researchers have reviewed their data and have found no increase mortality in their aggressive treatment group so far and their study continues.
FDA Actions
The FDA has approved bevacizumab (Avastin) for first-line treatment of women with metastatic HER2-negative breast cancer. When used in combination with paclitaxel, disease progression was reduced by 52% compared to treatment with paclitaxel alone. The approval was done under the FDA's accelerated approval program. Bevacizumab is manufactured by Genentech Inc.
The FDA has issued an early communication about an ongoing safety review of botulinum toxin Type A (Botox) and Type B (Myobloc) regarding reports of systemic adverse reactions including respiratory compromise and death. The reactions are suggestive of botulism. Many of these events occurred in children treated for cerebral palsy-associated limb spasticity, although reports of occurred for other uses in adults as well. The FDA's warning of health care professionals to watch for systemic effects as much as one day after injections including dysphasia, dysphonia, weakness, dyspnea or respiratory distress.
Note: The February 2008 issue of Pharmacology Watch stated that Bystolic was marketed by Mylan Bertek. It should be noted that Bystolic is marketed by Forest Laboratories as well.
This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5413. E-mail: [email protected].
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