New Study on Thiazolidinediones May Show Benefits
In this Issue: Pioglitazone and heart disease; ARBs manufacturers spend millions to show the non-inferiority of their products compared to less expensive, generic ACE inhibitors; some athletes turn to growth hormone because it is difficult to detect; FDA Actions
The thiazolidinediones rosiglitazone (Avandia) and pioglitazone (Actos) have taken their lumps in the last year, with evidence associating drugs with increased risks of heart failure. Rosiglitazone has also been associated with increased cardiovascular mortality, while evidence suggests that pioglitazone may actually improve cardiovascular outcomes. Now a new study compares pioglitazone with the sulfonylurea glimepiride measuring the progression of coronary atherosclerosis in patients with type 2 diabetes. A total of 543 patients with type 2 diabetes and coronary disease underwent coronary intravascular ultrasonography and were then randomized to receive glimepiride 1 to 4 mg daily or pioglitazone 15 to 45 mg daily for 18 months with titration to a maximum tolerated dosage. Intravascular ultrasonography was repeated in 360 patients at completion of the study. The primary endpoint was percent change in atheroma volume (PAV). Patients were also treated with standard therapy (statins, renin-angiotensin blockers, and aspirin). Glimepiride resulted in an increase in PAV of 0.73% (95% CI, 0.33%-1.12%) while pioglitazone decreased PAV by 0.16% (95% CI, -0.57% to 0.25%) (P=.002). Blood sugar control as measured by HbA1c was similar in both groups. Pioglitazone also resulted in increase in HDL cholesterol of 5.7 mg/dL compared to 0.9 mg/dL for glimepiride (P<.001), and pioglitazone lowered triglyceride levels an average of 16.3 mg/dL compared to an increase of 3.3 mg/dL with glimepiride (P <.001). Hypoglycemia was more common in the glimepiride group while edema, fractures, and decreased hemoglobin levels were more frequent in the pioglitazone group. The authors conclude that in patients with type 2 diabetes and coronary artery disease, pioglitazone slows progression of coronary atherosclerosis compared to glimepiride (JAMA 2008; 299: 1561-1573). An accompanying editorial points out that outcomes such as those found in the study may not translate to improving cardiovascular outcomes, however the results are consistent with a modest clinical benefit demonstrated in the PROACTIVE trial (JAMA 2008; 299:1603-1604).
ARBS effective as ACE?
Are angiotensin-receptor blockers (ARBs) as effective as angiotensin-converting-enzyme (ACE) inhibitors in reducing vascular events in high-risk patients? Manufacturers of ARBs have spend millions trying to show the non-inferiority of their products compared to the less expensive, generic ACE inhibitors. The current entry funded by Boehringer Ingelheim, the ONTARGET trial, compares their product telmisartan (Micardis) with the ACE inhibitor ramipril. In this large double-blind randomized trial of 25,000 patients with vascular disease or high risk diabetes, over 8500 patients received ramipril 10 mg per day, telmisartan 80 mg per day, or the combination of both drugs. The primary outcome was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure. Mean blood pressure was slightly lower in the telmisartan and combination therapy group than in the ramipril group. After a median follow-up of 56 months, the primary outcome occurred in 16.5% of the ramipril group, 16.7% of the telmisartan group, and 16.3% of the combination group. The ramipril group had a higher incidence of cough and angioedema, while the telmisartan group had a higher rate of hypotensive episodes. The combination group had a higher risk of hypotensive episodes, syncope and renal dysfunction compared to the ramipril group. The authors conclude that valsartan was equivalent to ramipril in patients with vascular disease or high risk diabetes, and was associated with less angioedema. There was no benefit in the combination of the two drugs (NEJM 2008; 358: 1547-1559). An accompanying editorial points out the difficulty in interpreting non-inferiority trials. In this study telmisartan preserved 94% of the benefit of 10 mg of ramipril (95% CI, 85 to 105). It is also the fourth trial showing that combinations of ACE inhibitors and ARBs are of no value in reducing cardiovascular events compared to ACE inhibitors alone. The author concludes that the ARBs provide a similar benefit to prevent ACE inhibitor therapy; however "because ARBs are more costly than ACE inhibitors and have more side effects, their primary value is as an alternative for patients who cannot tolerate ACE inhibitors because of cough." (NEJM. 2008; 358:1615-1616).
Athletes and Growth Hormone
As testing for performance-enhancing drugs becomes more prevalent in sports, some athletes have turned to growth hormone because it is difficult to detect. Touted as an anabolic agent that improves athletic performance, the drug is also associated with significance side effects including diabetes, hepatitis, and acute renal failure. Recently a group from Stanford performed a meta-analysis of 44 articles describing 27 study samples in which 303 participants received growth hormone representing 13.3 person-years of treatment. Participants were average 27 years old with lean body mass and physically fit. Lean body mass increased with growth hormone compared to participants who did not receive it (increase 2.1 kg 20.1 kg [95% CI, 1.3 to 2.9 kg]), however strength and exercise capacity did not improve. Lactate levels during exercise were statistically significantly higher in two of three studies, and growth hormone treated participants experienced soft tissue edema and fatigue more often than those who did not receive it. The authors conclude that claims that growth hormones enhance physical performance are not supported by the scientific literature. The drug may increase body mass but it is does not improve strength, and it may worsen exercise capacity and adverse events (Ann Int Med, early online release 18 March 2008, print date 20 May 2000).
Cefixime (Suprax), the only CDC recommended oral treatment for gonorrhea, is now available for the first time since 2002 in a 400 mg tablet. Wyeth Pharmaceuticals discontinued production of the drug when its patent expired. Now Lupin Pharmaceuticals has received FDA approval to market the 400 mg tablets. The company has been marketing the oral suspension since 2004. Cefixime 400 mg as a single dose is recommended treatment for all types of gonorrhea infections (urogenital, rectal, and pharyngeal).
The FDA has approved methylnaltrexone bromide (Relistor) for the treatment of opioid-induced constipation in patients with late stage, advanced illness who are receiving opiates on a continuous basis. The injectable medication is started on an every-other-day basis, then increased to once a day as needed.
The FDA has approved a new biologic, certolizumab (Cimzia) for the treatment of Crohn's disease. Certolizumab is a TNF blocker similar to other drugs used for this indication. The initial dose is one injection every two weeks for the first three injections, then decreasing to once every four weeks. Like other TNF blockers, certolizumab is associated with increased risk of serious infections, lymphomas, and other malignancies.
The FDA has investigated reports of increased depression in patients switched from Wellbutrin XL 300 mg to Teva's generic bupropion XL 300 mg (Budeprion). Nearly 80 patients of the thousands who were changed to the generic noted loss of antidepressant effect following the switch. The agency reevaluated bioequivalency studies and concluded that, although there are small differences in the kinetic profiles the two formulations they were within the establish boundaries of equivalents. They conclude that the generic is bioequivalent and therapeutically equivalent to the branded product.
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].Pioglitazone and heart disease; ARBs manufacturers spend millions to show the non-inferiority of their products compared to less expensive, generic ACE inhibitors; some athletes turn to growth hormone because it is difficult to detect; FDA Actions
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