Tag Archives: pioglitazone

Diabetes Drug Rosiglitazone About to Be Pulled Off the Market?

ResearchBlogging.orgIt’s over for rosiglitazone.

Sold in the U.S. as Avandia, rosiglitazone is a drug used to control type 2 diabetes either alone or in combination with insulin, metformin, or a sulfonylurea.  It has only one competitor in its class: pioglitazone (sold as Actos).

Both drugs in the thiazolidinedione class (aka TZDs or glitazones) increase the risk of heart failure.  Prior studies had suggested that rosiglitazone increases the risk of heart attack, heart failure, and death.  Research suggested that pioglitazone actually reduces the risk of heart attack, stroke, and death.

A study just published in the Journal of the American Medical Association directly compared clinical use of rosiglitazone and pioglitazone.  Investigators looked at Medicare data involving over 227,000 patients, average age 74, average follow-up of 105 days.

Rosiglitazone comes out the loser: users had significantly higher risk of stroke, heart failure, and death.  Risk of heart attack trended a bit higher in the rosi users but did not reach statistical significance. 

The researchers also calculated the composite risk of suffering either a heart attack, stroke, heart failure, or death:  rosiglitazone risk was about 18% higher compared to pioglitazone. 

What do these numbers mean from a practical viewpoint?  The researchers calculated a “number needed to harm.” Treat 60 patients with rosi and 60 with pio for one year; the rosi group will have one extra event—heart attack, stroke, heart failure, or death—compared with the pio users.

Why put up with that risk?  There’s no good reason.  Especially when pioglitazone is available.

Implications

If you take rosiglitazone, ask your doctor to find an alternative or switch you to pioglitazone.  Soon.

Clearly, we don’t know all of the adverse effects of many of the drugs doctors prescribe, whether for diabetes or other illnesses.  We balance the good with the bad, and that equation changes over time. 

Rosiglitazone’s manufacturer may pull the drug off the market voluntarily.  If not, the FDA will do it.  Cardiovascular disease—e.g., heart attacks, strokes, heart failure—kills 68% of diabetics.  The last thing we need is a drug that increases that risk.

Within a month, you’ll see ads on U.S. television from trial lawyers asking if you or a loved one has been hurt by rosiglitazone.  “If so, call this toll-free number now…”

Steve Parker, M.D.

Reference: Graham, D., Ouellet-Hellstrom, R., MaCurdy, T., Ali, F., Sholley, C., Worrall, C., & Kelman, J. (2010). Risk of Acute Myocardial Infarction, Stroke, Heart Failure, and Death in Elderly Medicare Patients Treated With Rosiglitazone or Pioglitazone JAMA: The Journal of the American Medical Association DOI: 10.1001/jama.2010.920

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Drug Review: Thiazolidinediones (pioglitazone, rosiglitazone)

pioglitazone and rosiglitazone for type 2 diabetesThiazolidinediones are more easily referred to as TZDs or glitazones.  Compared to the usual first-choice drug for type 2 diabetes (metformin), the TZDs are significantly more expensive.

Remember that drug names—both generic and brand—may vary depending on country and manufacturer.  In the U.S., rosiglitazone is sold as Avandia; pioglitazone is Actos. This is just a brief overview: consult your physician or pharmacist for full details.

How do they work?

In short, TZDs increase glucose utilization  and decrease glucose production, leading to lower blood sugar levels.  They sensitize several tissues to the effect of insulin.  Insulin, among other actions, helps put circulating blood sugar into our muscles, fat cells, and (to a lesser extent) liver cells.  So blood sugar levels fall.  Thiazolidinediones (aka TZDs) make these tissues more sensitive to this effect of insulin.  Insulin also suppresses glucose production by the liver, an effect enhanced by TZDs.  They reduce insulin resistance.

TZDs may also help preserve pancreas beta cell function.  Beta cells produce insulin.

They reduce both fasting and after-meal glucose levels.  Fasting blood sugar drops and average of 40 mg/dl.  Hemoglobin A1c falls by 1 to 1.5% (absolute, not relative).

TZDs tend to improve blood lipids: lower triglycerides, higher HDL cholesterol, decreased small, dense LDL cholesterol.  Pioglitazone has the more pronouned effect.

On a cellular level, they activate peroxisome proliferator-activated receptor-gamma, so they are sometimes referred to as PPAR-gamma agonists.  Pioglitazone also affects PPAR-alpha.

Uses

TZDs can be used alone or in combination with insulin, metformin, and sulfonylureas in people with type 2 diabetes.

Dosing

Note that onset of action is delayed by several weeks, perhaps as many as 8-12 weeks.

Pioglitazone:  Start at 15-30 mg/day by mouth.  Maximum dose is 45 mg/day.

Rosiglitizone:  Start at 4 mg/day by mouth.  After 8-12 weeks, dose may be increased to 8 mg/day.

Side effects

Weight gain is fairly common, through both fluid retention and increase in fat tissue.  Weight gain with pioglitazone, for example, is around 6–12 pounds (3–5 kg).  Mild anemia and puffy feet and hands (edema from fluid retention) are also seen.  Fluid retention may ultimately cause congestive heart failure.  This drug-induced fluid retention does not respond very well to fluid pills (diuretics).

The combination of insulin injections and TZD may increase the risk of heart failure.

Some studies suggest that rosiglitazone increases the risk of heart attacks, heart failure, and death.  That’s why the Food and Drug Administration in 2011 drastically curtailed use of the drug. The FDA re-examined the date in 2013 and decided that rosiglitazone didn’t increase cardiovascular risk after all.

Preliminary data suggest a link between bladder cancer and pioglitazone.

TZDs are associated with increased risk for broken bones, perhaps doubling the risk.

Macular edema—manifested by blurry vision—may occur infrequently.

When used as the sole diabetic medication, TZDs do not cause hypglycemia.  But when used with insulin injections or insulin secretagogues, low blood sugar can occur.

Don’t use if you . . .

. . . have a significant degree of congestive heart failure or active liver disease.  Even a history of heart failure may be a reason to avoid TZDs.  TZDs should probably not be used in women with low bone density or anyone else prone to fractures.

Steve Parker, M.D.

Updated December 26, 2013

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TZDs Associated With Broken Bones

You do NOT want this hip bone to break!

You do NOT want this hip bone to break!

A study presented at the 2009 Scientific Sessions of the American Diabetes Association associated thiazolidinedione drugs with a 40% higher fracture risk. 

Thiazolidinediones used in the U.S. are rosiglitazone (Avandia) and pioglitazone (Actos).  “Thiazolidinedione” is so hard to pronounce that my physician colleagues refer to them as “TZDs” or “glitazones.” 

The researchers examined the Medco database – more than 13 million people – looking for people with diabetes between the ages of 43 and 63 at study onset who were using TZDs, metformin, exenatide (Byetta), or a sulfonylurea (e.g., glipizide, glyburide, glimiperide).

Note that this study has not yet undergone the peer-review process and been published in a medical journal.

Take-Home Points 

These results are prelimary and require confirmation and peer-review by experts in the field.  Nevertheless, if I had diabetes and were at risk of broken bones –  presence of osteoporosis, for example – I would ask my doctor about alternatives before taking TZDs.  Stay alert for developments.   

Steve Parker, M.D.

Reference:  Wood, Shelley.  More evidence links glitazones to broken bones.  TheHeart.org, June 12, 2009.

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