All that Glitas is Not Gold – Musings on Pharma Marketing & Type 2 Diabetes
In the past several years, the second-generation glitazones Avandia (rosiglitazone) and Actos (pioglitazone) – once touted as breakthroughs that could reduce cardiovascular mortality in patients with type 2 diabetes – have been tarnished by controversy. 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 Rezulin’s withdrawal , in 1997 in the United Kingdom and in the United States in 2000.
The bad and the ugly about TZDs is that despite the fact that glitazones have not lived up to their potential and despite the fact that leading American diabetologists have stated publicly that their risks outweigh their benefits (particularly in the case of rosiglitazone), the drugs continue to be aggressively promoted and prescribed.
Many readers will peg the debate regarding glitazone safety to Dr. Steve Nissen’s 2007 meta-analysis in NEJM indicating that rosiglitazone increases the risk of myocardial infarction (MI) by 43%. Not everyone agreed with Dr. Nissen’s conclusions and there continues to be debate and disagreement over the cardiac safety of rosglitazone and the significance of PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events). PROactive is a study whose methodology sparked debate when the investigators substituted a more favorable secondary endpoint for a primary endpoint that failed to reach statistical significance. A critique of PROactive is elucidated in this commentary in Clinical Diabetes by Dr. Jay Skyler.
While diabetologists may disagree about the cardiac risks of rosiglitazone, virtually every thought leader, and reputable drug information source, concludes that rosiglitazone and pioglitazone increase the risk of heart failure and fractures. In 2009, these findings led the American Diabetes Association to release consensus guidelines unanimously advising against the use of rosiglitazone.
What is less well known is that the second-generation glitazones – which cause weight gain and edema and significant adverse events – 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 now seem 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 U.S. pharmaceutical companies conducted animal research to elucidate the mechanisms of action for rosiglitazine and pioglitazone [e.g. peroxisome proliferator-activated receptor (PPAR) 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 the 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 GSK funded the research and that 3 of the 4 authors were paid advisors to, or owned stock, in the company.
The later 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 glucose lowering alone. Since cardiovascular disease is the leading cause of death in 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 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. This observational study, however, co-authored 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 impact 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 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 American Diabetes Association (ADA)
The recent years – The glitazones lose their luster
Glitazones’ association with fluid retention started to appear in the literature as early as 2002-2003. 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. John Buse first presented negative data about rosiglitazone back in 1999, senior executives at GSK tried to get him fired from his job, accusing him of being a liar and stating that he was 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 treatment of type 2 diabetes. These new guidelines recommend that rosiglitazone not be used. This time, GSK says very little other than defending Avandia in a letter to the editor and stating that “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 without clear advantages are aggressively marketed, and prescribed, even though they have no proven benefits over older, existing treatments. In the past, drug companies had so much clout – and so much marketing muscle- that they could effectively drown out naysayers with multi-million dollar advertising campaigns and educational programs. Now the tide seems to be turning, although I cannot say for sure how many primary care physicians, who treat most patients with type 2 diabetes, have read the 2009 ADA guidelines.
All these musings remind me of that age-old riddle, “If a tree falls in the forest and no one hears it, did it really fall?” Medical evidence is a bit like that proverbial tree – whether physicians hear it depends on whether a pharmaceutical company will benefit from the sound of the fall. When clinical data promotes use of a drug, manufacturers will go our of their way to make sure that doctors hear about it – in advertising, medical education, scientific articles and speaker programs. In contrast, medical evidence with the potential to negatively impact sales often falls on deaf ears.