Widely prescribed diabetes drug falls short of promise, says new review

October 18, 2006

A new systematic review calls into the question the health benefits versus risks of an oral medicine widely prescribed for diabetes throughout the United States, Canada, Europe and Asia.

The drug - called pioglitazone - is marketed in the United States by Takeda Pharmaceuticals North America, Inc., and Eli Lilly and Co. under the trade name Actos.

"Our results showed that published scientific studies of at least 24 weeks of pioglitazone treatment in people with type 2 diabetes mellitus did not provide convincing evidence that patient-oriented outcomes like mortality, morbidity, adverse effects and health-related quality of life are positively influenced by this drug," said lead author Bernd Richter, M.D.

"Until new evidence becomes available, the benefit-risk ratio of pioglitazone therapy in type 2 diabetes mellitus remains unclear," added Richter, assistant professor in the department of endocrinology, diabetes and rheumatology at Heinrich-Heine University in Düsseldorf, Germany.

According to Richter, not only did the review demonstrate no clear-cut benefit to using pioglitazone, but it also showed an increased occurrence of edema and heart failure - including heart failure requiring hospital admission - among patients taking the drug.

The review appears in the current issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.

For the review, the authors analyzed the results of 22 randomized clinical trials involving 6,200 patients with type II diabetes receiving pioglitazone treatment. The longest duration of pioglitazone therapy received by any patient was 34.5 months.

Pioglitazone is one drug in a class of medicines called "thiazolidinediones," which are said to increase the body's sensitivity to insulin produced naturally by the body, thereby allowing better uptake of glucose into the cells of the body and lowering blood glucose levels.

Physicians in the U.S. prescribe drugs such as Actos to patients with type II diabetes, whose bodies either do not produce enough natural insulin or don't use the insulin as effectively as those not affected by diabetes.

HbA1c, or hemoglobin A1c, is a blood test that assesses a patient's blood glucose levels over time. The HbA1c number correlates with average blood glucose levels during the preceding 120 days, and most tellingly, during the previous eight to 12 weeks.

The review found that pioglitazone lowers HbA1c, but when compared to other active glucose-lowering drugs, similar reductions of HbA1c were achieved, so that "no apparent advantage of pioglitazone treatment could be demonstrated," said Richter. "Probably, the best comparison would be with metformin, where pioglitazone lowered HbA1c between 1.3 percent and 1.4 percent and metformin by 1.5 percent."

Pioglitazone has many possible side effects, including fluid retention, weight gain, and leg and ankle "edema" or swelling. In isolated cases it may lead to, or worsen, heart failure.

In the review studies, 15 percent of participants receiving pioglitazone therapy reported edema compared with 7 percent of participants in control groups.

The 15 studies that looked at body weight reported an increase of up to 8.6 pounds in those patients receiving pioglitazone treatment.

In one major study in the review, significantly more patients developed edema and heart failure, including heart failure needing hospital admission, following administration of pioglitazone - 6 percent versus 4 percent on placebo. Heart failure was reported in 11 percent of patients on pioglitazone therapy versus 8 percent on placebo.

The drug may also cause dangerous drops in blood glucose in people taking the drug in combination with insulin or another class of diabetes drugs called "sulfonylureas," which are marketed in the United States under the generic names glipizide, glyburide, glimepiride and chlorpropamide.

"The kernel from this review is that pioglitazone is effective in glucose-lowering, has some other beneficial and potentially harmful associated features and just has not been evaluated in the right way to prove that it will help people lead longer and more productive lives," said John Buse, M.D., director of the Diabetes Care Center at the University of North Carolina School of Medicine. "This is true for essentially every drug available for the treatment of diabetes."

"I am fairly certain that we are better off with pioglitazone than without it," Buse added. "We do not have proof but a great deal of signal that the benefits outweigh the risks. There are more data to come. The authors of the review are not incorrect in their assessments, but there is just not enough long-term data available in the literature to be certain of the benefits whereas the risks are much easier to assess."

"Pioglitazone treatment should be restricted to patients demonstrating real benefit of this therapy," Richter said. "Benefit should not be postulated on the basis of improvement of metabolic parameters like HbA1c reduction alone but should refer to patient-oriented outcomes such as fewer diabetic complications or better health-related quality of life."

Center for the Advancement of Health

---

---

	Differential Regulations of Lipid Profiles Between Japanese Responders and Nonresponders Treated with Pioglitazone (DOI: 10.3810/pgm.2011.01.2244) (Postgraduate Medicine) by JTE Multimedia The aim of this study was to evaluate the effects of pioglitazone on lipid profiles in relation to glycemic control. Eighty-one treatment-naïve patients with type 2 diabetes mellitus received pioglitazone monotherapy. Subjects who had ≥ 1% reduction in hemoglobin A1c (HbA1c) levels were defined as responders (n = 47) and those with < 1% reduction as nonresponders (n = 34). At 3 months, the HbA1c levels and several lipid parameters were compared with baseline values. Because it is known that the response to some antihyperglycemic agents is proportional to baseline HbA1c levels, the changes (Δ) in these parameters were compared for 2 groups based on their ΔHbA1c/baseline HbA1c ratio. The lowest tertile was called super-responders (n = 25) and highest tertile was called extreme...
	Pioglitazone: Webster's Timeline History, 1989 - 2007 by Icon Group International (Author) Webster's bibliographic and event-based timelines are comprehensive in scope, covering virtually all topics, geographic locations and people. They do so from a linguistic point of view, and in the case of this book, the focus is on "Pioglitazone," including when used in literature (e.g. all authors that might have Pioglitazone in their name). As such, this book represents the largest compilation of timeline events associated with Pioglitazone when it is used in proper noun form. Webster's timelines cover bibliographic citations, patented inventions, as well as non-conventional and alternative meanings which capture ambiguities in usage. These furthermore cover all parts of speech (possessive, institutional usage, geographic usage) and contexts, including pop culture, the arts, social...
	Pioglitazone improved lipids better than rosiglitazone.(Metabolic Disorders): An article from: Family Practice News by Mitchel L. Zoler (Author) This digital document is an article from Family Practice News, published by International Medical News Group on February 1, 2005. The length of the article is 520 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: Pioglitazone improved lipids better than rosiglitazone.(Metabolic Disorders) Author: Mitchel L. Zoler Publication: Family Practice News (Magazine/Journal) Date: February 1, 2005 Publisher: International Medical News Group Volume: 35 Issue: 3 Page: 23(1) Distributed by Thomson...
	Pioglitazone improves heart outcomes in diabetes.(News): An article from: Family Practice News by Miriam E. Tucker (Author) This digital document is an article from Family Practice News, published by Thomson Gale on October 1, 2005. The length of the article is 674 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: Pioglitazone improves heart outcomes in diabetes.(News) Author: Miriam E. Tucker Publication: Family Practice News (Magazine/Journal) Date: October 1, 2005 Publisher: Thomson Gale Volume: 35 Issue: 19 Page: 8(1) Distributed by Thomson...
	Recurrent MI down 28% in diabetics on pioglitazone.(Cardiovascular Medicine): An article from: Internal Medicine News by Bruce Jancin (Author) This digital document is an article from Internal Medicine News, published by International Medical News Group on December 15, 2005. The length of the article is 1068 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: Recurrent MI down 28% in diabetics on pioglitazone.(Cardiovascular Medicine) Author: Bruce Jancin Publication: Internal Medicine News (Magazine/Journal) Date: December 15, 2005 Publisher: International Medical News Group Volume: 38 Issue: 24 Page: 1(2) Distributed by Thomson...
	Pioglitazone improves CV outcomes in diabetics.(Endocrinology): An article from: Internal Medicine News by Miriam E. Tucker (Author) This digital document is an article from Internal Medicine News, published by Thomson Gale on October 1, 2005. The length of the article is 874 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: Pioglitazone improves CV outcomes in diabetics.(Endocrinology) Author: Miriam E. Tucker Publication: Internal Medicine News (Magazine/Journal) Date: October 1, 2005 Publisher: Thomson Gale Volume: 38 Issue: 19 Page: 32(1) Distributed by Thomson...
	Pioglitazone stalled thickening of the carotid in type 2 patients.(Cardiovascular Medicine): An article from: Family Practice News by Catherine Hackett (Author) This digital document is an article from Family Practice News, published by Thomson Gale on December 15, 2006. The length of the article is 765 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: Pioglitazone stalled thickening of the carotid in type 2 patients.(Cardiovascular Medicine) Author: Catherine Hackett Publication: Family Practice News (Magazine/Journal) Date: December 15, 2006 Publisher: Thomson Gale Volume: 36 Issue: 24 Page: 13(1) Distributed by Thomson...
	Pioglitazone blocked atherosclerosis in diabetics.(News)(Clinical report): An article from: Internal Medicine News by Catherine Hackett (Author) This digital document is an article from Internal Medicine News, published by Thomson Gale on December 1, 2006. The length of the article is 649 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: Pioglitazone blocked atherosclerosis in diabetics.(News)(Clinical report) Author: Catherine Hackett Publication: Internal Medicine News (Magazine/Journal) Date: December 1, 2006 Publisher: Thomson Gale Volume: 39 Issue: 23 Page: 8(1) Article Type: Clinical report Distributed by Thomson...
	Pioglitazone cut ischemic cardiac event rate by 17%.(Metabolic Disorders): An article from: Family Practice News by Bruce Jancin (Author) This digital document is an article from Family Practice News, published by International Medical News Group on October 1, 2008. The length of the article is 522 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available immediately after purchase. You can view it with any web browser. Citation Details Title: Pioglitazone cut ischemic cardiac event rate by 17%.(Metabolic Disorders) Author: Bruce Jancin Publication: Family Practice News (Magazine/Journal) Date: October 1, 2008 Publisher: International Medical News Group Volume: 38 Issue: 19 Page: 18(1) Distributed by Gale, a part of Cengage...
	Rosiglitazone risks outpace pioglitazone's in the elderly.(Metabolic Disorders): An article from: Family Practice News by Mary Ann Moon (Author) This digital document is an article from Family Practice News, published by International Medical News Group on December 15, 2008. The length of the article is 464 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available immediately after purchase. You can view it with any web browser. Citation Details Title: Rosiglitazone risks outpace pioglitazone's in the elderly.(Metabolic Disorders) Author: Mary Ann Moon Publication: Family Practice News (Magazine/Journal) Date: December 15, 2008 Publisher: International Medical News Group Volume: 38 Issue: 24 Page: 8(1) Distributed by Gale, a part of Cengage...