Podcasts about rosiglitazone

Finance ethics committee, big pharma with deep pockets, mafia like arrangements, and a patient with a 40% increase risk of ischemia myocardial events have in common? I will say todays podcast was inspired by a tweet, yes a tweet from Dr. john Mandrola and he said “I am embarrassed to have not (really) known the details of the rosiglitazone affair. Teaching this to learners has to be 10x more valuable than the krebs cycle. My gosh – talk about lessons to learn. We have to promote more skeptical priors’ He attached a link to a paper titled The rise and fall of rosiglitazone European Heart Journal, Volume 31, Issue 7, April 2010, Pages 773–776 https://academic.oup.com/eurheartj/article/31/7/773/433556 I also will say I did not know the details of the rosiglitazone affair but after spending the last 3 days digging through this paper and the sources to this paper and the sources to those papers and by the end you will know exactly what Finance ethics committee, big pharma with deep pockets, mafia like arrangements, and a patient with a 40% increase risk of ischemia myocardial events all have in common. This was a wonderful summary about rosiglitazone and the scandal of the mafia like drug company hiding and covering up the evidence in related to cardiac events…. For those of you that don’t know or are not medical roseglitizone is a diabetic drug, it part of the glipizide family and although rarely seen on medication this day in are it is a tragic and sickening story for a drug that was once the largest selling diabetes drug in the world. In 2006 sales of the drug reached over $3 billion. So when study came out in 2007 in the New England Journal of Medicine titled “effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes” which was a meta-analysis that sought to find if cardiovascular morbidity and mortality were decreased by rosiglitazone. Ultimately the results showed that those in the rosiglitazone group compared to those in the control group were 43% more likely to suffer a myocardial infarction ((((odds ratio for myocardial infarction was 1.43 (95% confidence interval [CI], 1.03 to 1.98; P=0.03), ))) and a trend towards increase rates of death from cardiovascular causes ((((1.64 (95% CI, 0.98 to 2.74; P=0.06) THAT IS A SHOW STOPPER—the top drug on the market for diabetes bringing in over 3 billion dollars actually causes heart attacks and death Of course GlaxoSmithKline, the maker of the drug came out and said, NO NO NO it is one trial and our drug is just as safe as any other diabetic drug. Hindsight we can all look back and say, “OMG are you kidding me, how did the FDA not step in right away’ and THAT is where the story begins. But in order to get to the beginning of the story to go back to 1998 when troglitazone was the only TZD glitazone on the market. Unfortunately, troglitazone was associated with rare but potentially fatal hepatotoxicity. This is obviously bad publicity in the FDA as well as all diabetics and physicians wanted better option. Insteps rosiglitazone= dysuria over drug was approved by the FDA after 5 trials consisting of just under 3000 patient’s. - https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21071_Avandia_medr.pdf 2 of the studies were placebo controlled that only lasted 26 weeks 1 study was a double blind comparing RSG with glyburide to just glyburide lasted 52 weeks 1 study was a 26week study looking at the effects of either RSG or placebo added to metformin And the last A 26 week double blind study comparing metformin monotherapy vs RSG monotherapy vs RSG + metformin There you have it- the 5 trials that got RSG FDA approval. Just under 3000 patients and a grand total of 3 yrs TOTAL of data. One of the problems is a duration of these trials. A million one week trials is not equal to one trial that is a million weeks long. The hard outcomes need time to develop. It is like a good play action pass, it takes time to develop the play. Death and heart attacks take time to develop and short trials often miss these outcomes PLUS the trials were looking for……..A1C and FBS There are many problems with the A1C and FBS but the main one is the lack of association with A1C and hard end points. High A1C is bad, that seems pretty clear but as long as it is some what controlled the macrovascular risk does not appear to change very much. TO ApprovE diabetes drugs based on glycemic effects is not smart. Who cares if a drug lowers your blood suger but makes you 50% more likely to have a heart attack. Yet, we are obsessed with the number and the patient outcome. ((((((((((((The current SGLT2 inhibitors that are showing cardiovascular benefits change the A1C very little. A1C seems to be a surrogate marker we put way to much strength in when there is likely something else going on since it is clear A1C does not tell the whole picture but lets get back to RSG))))))) Of these 5 trials you will find that when you dig a little deeper into the numbers In 3-5 trials LDL cholesterol was increased by an average of almost 20% PLUS- There is also significant amount of weight gain with rosiglitazone in the 6 months trials those randomized to rosiglitazone gained almost 10 pounds more than those in the control group. Saying that differently, 20% of the patients randomized to rosiglitazone had gained 5-10% of the body weight at 6 months compared to only 2% of the patient’s placebo group and 1% of patients in the metformin group. BUT MAYBE the biggest problem was ---- And when you combine all 5 trials the rates of ischemic cardiovascular events were almost twice as likely in individuals receiving rosiglitazone compared to those randomized to the control arm. BUT good news, remember how I said, troglitazone was associated with fulminent hepatitis? Well it looks like RSG did not share this trait, there were no cases report! This is great news and remember FDA, patients and doctors want another option, they want a better option. And when you scroll down to page 40-41 of the medical officers review of a new drug for RSG you will read “Heart disease due to atherosclerosis is a major cause of morbidity and mortality in patients with type 2 diabetes, and it cannot be assumed that treatment with rosiglitazone will decrease the risk” the go on to say “my concern about deleterious long-term effects on the heart should be addressed by requiring a sponsor to provide adequate information in the label about changes in weight and lipids. A post marketing study to address these issues needs to be a condition of approval.” TWO big things happened right around this time— May 1999, FDA approval rosiglitazone Dr John Buse a diabetic special at UNC was speaking at an American Diabetes Association symposium where he called into question the cardiovascular safety of rosiglitazone Both of these things in and of themselves are not bad things. Sure the FDA hindsight should have required more data but their backs were against the wall so although I do point blame I don’t point a ton of blame. Dr. John Buse he is allowed to question medicine he is allowed to say hey I don’t think this is correct. But for every action there is an equal and oppisite reaction for the action of FDA approval of RGS the reaction was a ton of prescribing of RSG- Drug reps were in the office showing you how great this new drug is that does not cause liver failure and how it lowers your A1C blood test which we have all artificially made as the gold standard compared to any hard outcome. The drug reps would talk about how RSG lowered the CRAP marker….. wait did I just say crap marker?? Oooo sorry, I mean to say it lowered the CRP blood marker, but given the value of CRP I was probably right the first time. Sadly, we as physicians ate from their hands and prescribed a bunch of it. TONS of it. Over 3billion dollars of it. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2099503/ https://www.finance.senate.gov/imo/media/doc/prb111507a.pdf But remember I said for every reaction is equal and opposite well when Dr. John Buse spoke out against rosiglitazone is certainly triggered a reaction from glaxosmithkline… what kind of reaction you ask? Well they went after Dr. Buse with a team of lawyers and per paperwork given to the United states senate committee on finance it was clear that Dr. Buse was bullied into signing in agreement stating that he was no longer worried about cardiovascular risks associated with RGS. And he was barred from probably expressing concerns about safety of the drug in the future. The company was threatening to sue him for damages from his comments which glaxosmithkline was claiming cost them over 4billion dollars because of a stock price drop. Yes- this is 1999 and glaxosmithkline is acting like the mafia. They don’t care about the patients. They care about their 4billion in loss revenue. What is even more discussing is glaxosmithkline used this forced retraction letter to gain a foothold with financial investors. Some of the testimony and documents that were revealed in the senate finance committee will make you never want to prescribe another glaxosmithkline drug every again. Truly sickening. https://www.finance.senate.gov/imo/media/doc/prb111507a.pdf so we have this drug company, glaxosmithkline that knows they have a “bad drug’ or at least a drug that requires further investigation and evaluation but is doing everything they can to cover up or hide what leadership knows to be true. Likely for the world and patient’s everywhere in 2004 glaxosmithkline was sued over their drug paroxtine by the state of NY claiming they had not released or published the results of their unfavorable or negative trials on paroxtine. And I will get back to RGZ but stop me if you have heard this one before GSK runs 2 trial of paroxtine in adolescence, Study 329 conducted from 1993-1996 and at the itme was the largest trial to date for the use of SSRI in the pediatric population. In this study paroxetine didn’t beat placebo. The other study, Study 377, placebo was actually more effective than the antidepressant. However, instead of releasing these results there was an email that was later accidently leaked from within the corporation stated that because the results were “insufficiently robust“ the company needs to “effectively manage the dissemination of these data in order to minimize any potential negative commercial impact” The data was hidden or covered up and in 2003 paroxetine was a 4.9 billion dollar drug https://www.ncbi.nlm.nih.gov/pmc/articles/PMC343848/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC437671/ Luckily for us, when GSK settled this case, they wrote a check for 3 billion dollars, or roughly 9months of income from just the sales of paroxtine in 2003 and they agree to make a clinical registery that has all their data after dec 27 200. Are you asking how is this a good thing when a company that is bringing in deca-billions is hit with a measly 3 billion dollar fine?? Well then you don’t know how it ends, Now that the data was out there in a clinical registry you can do a study of And it turns out that is exactly what happened, a meta-analysis of 42 studies, 35 of which were unpublished. The authors poor over the data and submitted their paper for pubication to the all wonderful and incredibly high impact journal most of you have heard of called the NEJM. Now when you submit an article to a journal it has to undergo peer review process. Basically this is when other experts in the field or individuals with knowledge of the subject at hand review the paper to make sure all the T are crossed and I are dotted. When you peer Review of paper it is supposed to be secretive. He’ll share the document with anyone. Not even your best friend. Unfortunately one of the individuals that reviewed the paper, Dr. Steven Haffner at University of Texas in San Antonio, sent the analysis to GKS. Remember you don’t share this with your best friend let alone the DRUG COMPANY! This is a breach of ethics and every journal has rules on this and it certainly violates those. Why would someone do this??? Oooo maybe because Dr. Steven Haffner was getting paid by GKS, almost a $100,000 in total payment up to that point. This is the mafia, the mafia we see in movies, they cover up information and have every cop or ‘good guy’ in the city on their payroll. This NEJM of medicine article is the same one I mentioned at the beginning of this podcast, the article titled “effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes” which was a meta-analysis that sought to find if cardiovascular morbidity and mortality were decreased by rosiglitazone. And Ultimately the results showed that those in the rosiglitazone group compared to those in the control group were 43% more likely to suffer a myocardial infarction ((((odds ratio for myocardial infarction was 1.43 (95% confidence interval [CI], 1.03 to 1.98; P=0.03), ))) with a trend towards increase rates of death from cardiovascular causes ((((1.64 (95% CI, 0.98 to 2.74; P=0.06) THIS PAPER that was a show stopper for GSK they had in their hands 2 weeks prior to publication and they did their own statistical analysis and concluded that the numbers were spot on. They were not surprised by the findings. You may be asking why within not surprised by the findings? Well it’s because in 2006 GSK had already done their own analysis which found a 30-43% increase in ischemic events and this data was shared with the FDA who then did their own analysis and found a similar 40% increase in ischemic events.. However near the FDA nor GSK ever announced this information or released it to the medical community.. why would this happen you ask?? My guess is money but I couldn’t prove this to be true. “Music” How does this story end???? Eventually, 5 months after the meta-analysis published in the New England Journal of Medicine and almost an entire year after the FDA made there own similar conclusions about rosiglitazone they finally added a black box warning for increased risk of ischemic myocardial events. And remember when the drug was bring approved by the FDA and they said in the final analysis “. A post marketing study to address these issues needs to be a condition of approval.” Well it comes at no surprise the GSK knew this would be bad news for them so No well-designed cardiovascular outcome trials were conducted. The RECORD trial was the only cardiovascular outcome trial which look to compare cardiovascular outcomes and it was a seriously underpowered open label study with low adherence to medications, and not completed until 10 years following launch. HOWEVER the FDA mandated the study in 2007 after the release of internal documents and the adversory committee and the metaanalysis showing a 40% increase in ischemic cardiac events. It is no surprise this was big news and the trial struggled with slow enrolled because anyone who watched tv or read the news paper knew this was a bad drug and no provider wants to enroll a pt. on a drug that is knowingly harmful! https://www.nejm.org/doi/full/10.1056/NEJMoa066224 Ultimately the trial was halted in 2010 and I think for good reason, When you are a patient going into a trial hopefully you get a miracle cure drug and at worse you get placebo. In this trial you at best would get a placebo and at worst a harmful drug. Dr. Buse, the physician who made the initial statement and warning in 1999 and was shut up by the drug company?? Well, At a 2007 FDA safety panel meeting on RGS, FDA scientists presented data showing RGS was estimated to have caused approximately 83,000 excess heart attacks since coming on the market. If a scientist was able to speak freely and question medicine it is almost certain SOME of those heart attacks would have been prevented. https://www.finance.senate.gov/imo/media/doc/prb111507a.pdf Luckily, not all bad came from this story – it led a bunch of people to question medicine which I will forever be a fan of, I agree with Dr. John Mandrola we need to promote more skeptical learners. Also because of this in December 2008, the FDA issued a new guidance for development of drugs to treat diabetes, requiring cardiovascular outcomes trials. This is the reason we now have the SGLT2 inhibitors that seem to be working to prevent cardiovascular events. They didn’t know the outcome was going to be a decrease in events they were just hoping there was not an increase in cardiovascular events.

Brian, Katie, and I sit down with Vince Fuoco, a pharmacist from the greater Seattle area. We discuss a wide range of medication-related issues, including Coronavirus, dieting and nutrition, the placebo effect, the opioid crisis, and mental health. We also delve into a few less-scientific topics, drink fantastic beer from Geaux Brewing in Auburn, and much more! Recorded March 7th, 2020 at the TPDM studio in Wenatchee, Washington. Check out Vince Fuoco's podcast: Pick A Topic https://anchor.fm/vincent-fuoco/ Geaux Brewing -- Auburn, WA http://www.geauxbrewing.com/   EPISODE NOTES: Peramivir — an antiviral injection for treating influenza https://www.fda.gov/drugs/information-drug-class/rapivab-peramivir-information The Game Changers (documentary) https://en.wikipedia.org/wiki/The_Game_Changers The Complete Guide to Fasting: Heal Your Body Through Intermittent, Alternate-Day, and Extended Fasting (book by Jason Fung and Jimmy Moore) https://www.amazon.com/Complete-Guide-Fasting-Intermittent-Alternate-Day/dp/1628600012 https://www.dietdoctor.com/intermittent-fasting/guides Angus Barbieri's record-breaking fast https://en.wikipedia.org/wiki/Angus_Barbieri%27s_fast The Placebo Effect https://www.webmd.com/pain-management/what-is-the-placebo-effect Eddy Merckx — Belgian cycling legend https://en.wikipedia.org/wiki/Eddy_Merckx Magic Bullet Effect (medicine) http://broughttolife.sciencemuseum.org.uk/broughttolife/techniques/magicbullet Cure for Hepatitis C https://www.mayoclinic.org/medical-professionals/digestive-diseases/news/most-patients-with-hcv-cured-with-new-drugs-but-at-what-price/mac-20430491 Avandia (rosiglitizone) https://en.wikipedia.org/wiki/Rosiglitazone https://blogs.scientificamerican.com/observations/avandia-restricted-in-u-s-banned-in-europe/ Heroin marketed for children in the early 1900's https://www.narconon.org/drug-information/heroin-history-1900s.html The Pharmacist (documentary) https://www.netflix.com/title/81002576 Cigarette advertisements featuring physicians https://www.healio.com/hematology-oncology/news/print/hemonc-today/%7B241d62a7-fe6e-4c5b-9fed-a33cc6e4bd7c%7D/cigarettes-were-once-physician-tested-approved Washington State prescriptive authority for Narcan https://www.wsparx.org/page/NaloxoneOpioid https://stopoverdose.org/naloxone-law-in-washington/ Supervised consumption services in Switzerland JRE #1250 — Johann Hari https://www.youtube.com/watch?v=CDpjvFn4wgM&t=1722s Medical Heroin program in Norway https://www.theguardian.com/world/2018/aug/10/norway-trials-free-heroin-prescriptions-for-most-serious-addicts Ibogaine Therapy for drug addiction https://maps.org/research/ibogaine-therapy Ibogaine for treatment of alcoholism — clinical trial in Brazil https://www.clinicaltrials.gov/ct2/show/NCT03380728 Jay Greenberg — prolific composer and cello prodigy twice featured on 60 minutes https://en.wikipedia.org/wiki/Jay_Greenberg_(composer) Daniel Tammet — British man who memorized over 22,000 digits of Pi (π) https://www.sciencemag.org/news/2005/04/man-who-memorized-pi Medical Cannabinoids for Cancer Cachexia https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360413/ Marinol — brand name for dronabinol, a specific type of THC used for chemotherapy-induced nausea/vomitting https://en.wikipedia.org/wiki/Dronabinol https://medlineplus.gov/druginfo/meds/a607054.html Notes from Brian: Lisinopril is not a duretic. It's an angiotensin-converting enzyme (ACE) inhibitor. Furosemide is an example of a duretic which would have a fluid-reducing effect. The New England Patriots started four different quarterbacks in 1992. Hugh Millen, who played for the University of Washington in 1985, led the '92 Patriots in passing yards. Drew Bledsoe played high school football for the Walla Walla Blue Devils, not the Prosser Mustangs. https://www.thisprobablydoesntmatter.com/

In this podcast, Editorial Board member Elizabeth McInnes invites authors Evan Janovitz and Magnus Söderberg to discuss their article "Evaluation of Uracil, Sodium Ascorbate, and Rosiglitazone as Promoters of Urinary Bladder Transitional Cell Carcinomas in Male Sprague-Dawley Rats" featured in the February 2018 issue of Toxicologic Pathology.   Click here to read the article.

Human peritoneal mesothelial cells (MC) play an important role in inflammatory processes of the peritoneal cavity by producing various cytokines and chemokines, such as monocyte chemoattractant protein-1 (MCP-1). The present study was designed to assess the effect of the peroxisome proliferator-activated receptor-gamma- (PPAR gamma-) activator rosiglitazone on the mesothelial MCP-1 expression and release. Primary cultures of MC were obtained from omental tissue. MCP-1 antigen concentrations were measured in the cell supernatant by ELISA and MCP-1 mRNA levels by real-time polymerase chain reaction. The presence of PPAR. on MC was assayed in a Western Blot analysis. MC constitutively express PPAR gamma. Activation of this receptor via rosiglitazone (0,1-10 mu mol/L) resulted in significantly reduced amounts of mesothelial MCP-1 release as well as MCP-1 mRNA. The use of the PPAR gamma inhibitor GW-9662 could completely prevent the rosiglitazone effects. Rosiglitazone was also effective in reducing TNF alpha-induced enhanced secretion of MCP-1. Our findings indicate that glitazones are effective in reducing constitutive and TNF alpha-stimulated mesothelial MCP-1 mRNA expression and release.

Audio Journal of Medicine, July 16th 2007 Rosiglitazone for Patients with Diabetes: Cardiovascular Outcomes Trial Findings REFERENCE: N Engl J Med 2007; 357: 28-38 STUART POCOCK, London School of Hygiene and Tropical Medicine Reassuring findings about the safety of the anti-diabetic drug rosiglitazone have been published in the New England Journal of Medicine following an interim analysis of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study. This latest publication follows a meta-analysis in June 2007 by Nissen and Wolski which raised doubt about the safety of the drug. Nicola Solomon spoke with the RECORD trial’s statistician, Stuart Pocock, to get the latest data from this largest study specifically designed to look at cardiovascular outcomes.