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All that Glitas is Not Gold — Musings on Pharma Marketing & Type 2 Diabetes

The second-generation glitazones Avandia® (rosiglitazone) and Actos® (pioglitazone) — once touted as breakthrough drugs that could reduce cardiovascular mortality in patients with type 2 diabetes — were so tarnished by controversy that one of them (Avandia) was withdrawn from the market in UK, Spain, France, and Germany, although both drugs remain available in the United States.

The story of the glitazones (also known as thiazolidinediones or TZDs) reflects everything that is good, bad, and ugly about the pharmaceutical industry. When pharmaceutical manufacturers first started investigating rosiglitazone and pioglitazone, I am sure they had good intentions, thinking that these two agents would offer benefits over drugs like metformin. In the late 1990s, optimism about the potential of these second-generation TZDs grew as liver toxicity associated with troglitazone (Rezulin®, a first-generation TZD) resulted in the withdrawal of Rezulin in the United Kingdom in 1997 and the United States in 2000.

The bad and the ugly about TZDs was this: Despite the fact that glitazones did not live up to their potential, and despite the fact that leading American diabetologists stated publicly that the risks of these drugs outweighed their benefits (particularly in the case of Avandia/rosiglitazone), the drugs continued to be aggressively promoted and prescribed. In this 2016 press release, the FDA actually warned the public that Actos usage might be linked to bladder cancer and sales plummeted. Although the FDA has reversed this warning, clinical researchers continue to disagree about whether or not Actos increases the risk of bladder cancer. Some research says it does, while other research says it does not. 

Many readers will peg the debate regarding glitazone safety to Dr. Steve Nissen’s 2007 meta-analysis in NEJM, where he stated that rosiglitazone increases the risk of myocardial infarction by 43%. The debate and disagreement over cardiac safety of rosglitazone and Actos continued in a study dubbed PROactive (Prospective Pioglitazone Clinical Trial In Macrovascular Events). PROactive’s study methodology sparked questions when the investigators substituted a more favorable secondary endpoint for a primary cardiac endpoint that failed to reach statistical significance. A critique of PROactive is elucidated in this commentary by Dr. Jay Skyler in Clinical Diabetes.

While diabetologists disagreed about the cardiac safety of rosiglitazone, virtually every thought leader and reputable drug information source concluded that rosiglitazone and pioglitazone increase the risk of heart failure and fractures. In 2009, these findings led the American Diabetes Association (ADA) to unanimously advise against the use of rosiglitazone. Newer 2018 ADA guidelines provide lukewarm comments regarding low-dose pioglitazone.

One very interesting side note: These second-generation glitazones were originally positioned as being cardioprotective in patients with type 2 diabetes. In other words, they were touted to prevent the very problems that they later seemed to promote.

To understand how and why glitazones were launched with the perception of improved cardiac health, we need to go back to the early 1990s, when US pharmaceutical companies conducted animal research to elucidate the mechanisms of action for rosiglitazine and pioglitazone (e.g., peroxisome proliferator-activated receptor [PPAR]-gamma agonism) and to the late 1990s, when a diabetologist at University of North Carolina School of Medicine almost lost his job for disclosing negative data about rosiglitazone at a national medical conference.

The Early Years — Glitazones and Animal Research

In 1996, researchers investigating the effects of PPAR-gamma agonists discovered that adding pioglitazone to aortic rat smooth muscle cells inhibited abnormal cell proliferation. This research, published in American Journal of Hypertension concluded that glitazones may be more useful than commonly prescribed diabetes drugs such as metformin for inhibiting atherosclerosis, a process that frequently occurs in diabetic patients. In another article published that same year in American Journal of Physiology, researchers showed that when pioglitazone was administered to Dahl-S rats (an animal model for hypertension), the drug inhibited normal vascular responses to norepinephrine and angiotensin II. This, along with other studies conducted with troglitazone, opened up a wave of speculation that since PPAR-gamma agonists seemed to have a cardioprotective effect in diabetic rats, they had the potential to improve hypertension and cardiovascular disease progression in humans.

Fast forward to 1999, and we see more glitazone animal research appearing in the scientific literature. In one article, the authors examined the effects of rosiglitazone on blood pressure and endothelial function in fatty Zucker rats (an animal model for obesity, hypertension, and diabetes). The authors postulated that since rosiglitazone prevents hypertension in insulin resistant rats, the drug might reduce cardiac risks associated with obesity and insulin resistance in humans. What is apparent from reading this article in Diabetes, but is not apparent from the abstract is that GlaxoSmithKline (GSK) funded the research and three of the four study authors were paid advisors to or owned stock in the company.

The Mid Years — Glitazones and Surrogate Endpoints

With the launch of Avandia and Actos in 2000, GSK and Merck continued their efforts to show that pioglitazone and rosiglitazone could prevent complications beyond those achievable by lowering glucose alone. Since cardiovascular disease is the leading cause of death in people with type 2 diabetes, the possibility that glitazones might prevent heart attacks or strokes in patients with diabetes was very exciting. As with many pharmaceutical agents, the focus of this industry research was “surrogate endpoints.” In other words, clinical researchers tried to suggest that glitazones could reduce cardiac morbidity and mortality by showing that the drugs impacted surrogate measures of cardiac disease, primarily triglycerides, LDL, and HDL cholesterol. This research produced conflicting reports. While studies like this retrospective study of medical records from 605 primary care practices suggested that pioglitazone improved LDL, HDL, and triglycerides, the findings for rosiglitazone were not so rosy. In contrast, this observational study coauthored by a Glaxo employee concluded that “no differences in changes in LDL-C or HDL-C could be discerned between patients treated with rosiglitazone compared with pioglitazone.” Finally, while research showed that pioglitazone did exert favorable impacts on lipids, there was no certainty that such improvements in surrogate endpoints would translate into improved clinical endpoints. Around this time, rosiglitazone received another blow when Dr. John Buse, a prominent endocrinologist from University of North Carolina School of Medicine, presented negative findings about the drug at national medical conferences of the Endocrine Society and the ADA. 

The Later Years — The Glitazones Lose Their Luster

Glitazones’ association with fluid retention started to appear in the literature as early as 2002. By 2008, a steady stream of clinical publications linked glitazones with congestive heart failure. Additional data indicated that the drugs increased the risk of fractures in women.

When Dr. Buse first presented negative data about rosiglitazone back in 1999, senior executives at GSK tried to get him fired, accusing him of being a liar and accountable for a $4 billion dollar loss in market capitalization. The Senate Finance Committee’s Report on the incident can be found here. Fast forward to 2009, and John Buse is a member of the ADA consensus committee issuing national guidelines on the treatment of type 2 diabetes. These guidelines recommended that rosiglitazone not be used. This time, GSK did very little other than defend Avandia in a letter to the editor , stating “GlaxoSmithKline regrets the recommendation of the recent American Diabetes Association/European Association for the Study of Diabetes consensus statement against the use of rosiglitazone for treatment of type 2 diabetes because it is contrary to scientific evidence.”

Because prescription drug sales are so profitable, many medications are aggressively marketed and prescribed, even though they have no proven benefits over older treatments. In the past, drug companies had so much clout — and so much marketing muscle — that they could drown out naysayers with multimillion dollar advertising campaigns and educational programs. The glitazone controversies eventually tarnished these drugs; however, this only occurred 10 years post launch. When the glitazones market crashed, new classes of diabetes drugs stepped in to fill the void.

These musings about the marketing of drugs for diabetes reminds me of the line from Shakespeare’s Merchant of Venice: “All that glitters is not gold.” Drug company marketing departments introduce their new “shiny” treatments with much fanfare. Years later, many of these drug breakthroughs become tarnished as newer data and information comes out. 

Manufacturers bombard us with favorable information about their new products — in advertising, medical education, scientific articles, and speaker programs — in order to help their products quickly get absorbed into mainstream medicine. In contrast, more balanced and often negative evidence is only heard years later. Our society must find a way for the skeptics and naysayers to make their voices heard sooner. Whether talking about diabetes, COPD, or opioids, we need to find counterbalance to the golden and rosy perspectives of drug advertisers.