Avandia Lawyer - Avandia Side Effects - Avandia Lawsuit - Avandia Heart Attack - Avandia Attorney

Thiazolidinediones have a role for appropriate diabetic patients

-Heartwire

10/20/2009 - Although the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial and other trials found that rosiglitazone (Avandia, GlaxoSmithKline) increases risk of heart failure and fractures, thiazolidinediones (TZDs) are still useful for appropriate diabetic patients. This was the message from four speakers here at the International Diabetes Federation (IDF) 2009 World Diabetes Congress.

After 10 years of clinical use of the TZDs—rosiglitazone, pioglitazone (Actos, Takeda Pharmaceuticals North America), and the discontinued troglitazone—"are we at the end?" Dr Bart Staels, (Institut Pasteur de Lille, Lille, France) asked rhetorically.

"I think we are at the beginning" of clinical use of these peroxisome proliferator-activated receptor-gamma (PPAR-) agonists, Staels said. He hopes that second- and third-generation drugs will be developed that have all the benefits—such as improved insulin sensitivity—without the adverse side effects of the current first-generation drugs.

Two years ago, Dr Steven E Nissen (Cleveland Clinic Foundation, OH) and statistician Kathy Wolski (Cleveland Clinic) "dropped a bomb," Staels noted, when they published a meta-analysis showing that rosiglitazone poses a significant increased risk of MI [2]. This led to hot debates about the merits of TZDs and of the meta-analysis itself.

Undesirable effects of the first generation of these drugs—edema, weight gain, and increased risk of bone fractures—had already been seen in preclinical animal studies, Staels noted.

Nevertheless, ongoing research in this class of drugs is "very exciting," he said, adding that when researchers are developing novel PPAR agonists, risks for each compound should be viewed on a case-by-case basis, since compounds in this drug class have distinct differences.

For the RECORD

Discussing the recently published RECORD trial results (which were previously reported by heartwire), coinvestigator Dr Henning Beck-Nielsen ( Odense University Hospital, Denmark) said, "RECORD presents very clear data of the equivalence of rosiglitazone to metformin and sulfonylurea therapy" when used as an insulin sensitizer for glucose lowering.

However, rosiglitazone is not recommended in people with a history of heart failure, and RECORD confirms rosiglitazone increases the risk of some fractures, mainly in women, he added.

"What is new is that we have now looked into not only cardiovascular death and cardiovascular hospitalization, but also all types of cardiovascular disease—acute coronary syndrome, angina, and so on—and still rosiglitazone is not inferior to standard glucose-lowering drugs," he told heartwire.

RECORD randomized 4447 people with type 2 diabetes who were taking metformin or sulfonylurea monotherapy to add-on rosiglitazone or to a control group of metformin and sulfonylurea, he said. During a mean follow-up of 5.5 years, 321 people in the rosiglitazone group and 323 people in the control group experienced the primary outcome—time to first cardiovascular hospitalization or cardiovascular death—showing noninferiority.

However, 10 people in the rosiglitazone group vs only two people in the metformin/sulfonylurea group died of heart failure. Significant predictors of death from heart failure included age older than age 60, waist circumference greater than 104 cm, existing increased albumin excretion, and being treated with beta blockers.

The Bypass Angioplasty Revascularization Investigation Type 2 Diabetes ( BARI 2D) trial, showed that even diabetic patients with MI benefit from the drug, Beck-Nielsen told heartwire. He cautioned, however, that physicians need to assess each patient's risk of fractures, and if needed, prescribe bisphosphonates.

"Reassuring" randomized trials

Discussing cardiovascular disease in long-term trials of PPAR-agonists, Dr Lawrence A Leiter ( University of Toronto, ON) said: "There is no conclusive evidence from prospective randomized controlled trials specifically designed to evaluate cardiovascular effects of rosiglitazone (RECORD, BARI 2D) or that included rosiglitazone (ACCORD, VADT) that rosiglitazone is associated with increased cardiovascular risk." Ongoing clinical trials should resolve the specific cardiovascular effects of the PPARs, he added.

"I think we shouldn't get distracted by meta-analyses that have inherent limitations, and the large randomized controlled trials have been very reassuring to date," he told heartwire.

The TZDs are effective glucose-lowering agents, he said, and results from early meta-analyses of studies not designed to assess cardiovascular outcomes and from observational studies are mixed. There is no conclusive randomized controlled trial evidence that pioglitazone is associated with decreased cardiovascular risk.

"The Thiazolidinediones Intervention with Vitamin D Evaluation [TIDE] study is designed to give us the definitive answer, but in the meantime, I'm reassured by the data, and I'll continue to use both thiazolidinediones in appropriate patients—diabetic patients with high glucose despite metformin and with no contraindications to a thiazolidinedione such as heart failure," Leiter told heartwire. TIDE is designed to answer the question "Does adding thiazolidinedione up to 5.5 years reduce MI, stroke, or cardiovascular death?" he added.

"The take-away message is that looking at the totality of evidence, there's certainly no convincing signal of increased cardiovascular risk associated with rosiglitazone," Leiter said.

Brittle bones, TIDE will tell

"The rapidity of bone loss and the extent of the increase of fracture incidence suggest that fracture risk assessment should be undertaken in most individuals using thiazolidinediones," Dr Ian Richard Reid ( University of Auckland, New Zealand), discussing TZDs and bones, said.

To manage patients on TZDs and assess fracture risk, bone-density measurement gives about half of the risk, he noted. The other risk comes from age (a woman in her 80s has a 10- to 20-fold higher risk than a woman in her 50s), weight, prior fracture, smoking, and family history. FRAX, a helpful fracture risk-assessment tool from the WHO, is available on the internet, he added.

Commenting on the session to heartwire, symposium cochair Dr Amir Hanna ( University of Toronto) said: "We went through the randomized controlled trials on thiazolidinediones, comparing thiazolidinediones with other agents, and found conclusively that there is no increase in mortality and no increase in cardiovascular mortality." There is definitely an increase in congestive heart failure with these agents, which was already well-known, and fractures are a concern that needs further study, he added.

"I hope that the TIDE study will tell us some information about how to treat patients on thiazolidinediones," Hanna concluded.

If you or a loved one have experienced an Avandia heart attack, or Avandia stroke, Avandia congestive heart failure, Avandia cardiovascular disease or if you have lost a loved one to an Avandia death you may be entitled to compensation. Contact the Avandia attorneys of Ennis & Ennis today for a free confidential case evaluation. Our on staff nurse and lawyers are standing by to answer any questions you may have regarding Avandia's side effects, a possible Avandia class action lawsuit, or any other type of Avandia litigation.