I’m just learning about this drug, looks interesting.
Here is a summary of the commercial history of pioglitazone — key patent milestones, regulatory approvals, launches, genericization, safety/regulatory changes, and current status.
Origins & Patenting
Pioglitazone is a thiazolidinedione class drug, developed by Takeda and co-developed with Eli Lilly in some markets. (PMC)
In the United States, the Food and Drug Administration (FDA) approved Actos (pioglitazone hydrochloride) on July 15, 1999 for the treatment of type 2 diabetes mellitus. (FDA Access Data)
In Europe, approval through the European Medicines Agency (EMA) came about a year later, on October 13, 2000. (PMC)
Its launched brand name in the U.S. is Actos. (Wikipedia)
Commercial Performance / Sales
Early expectations: when it was launched, pioglitazone was seen as a safer thiazolidinedione than its predecessor drugs (such as troglitazone, withdrawn for liver toxicity), with hopes of considerable sales. (WIRED)
It in fact became a blockbuster drug; at various points, its sales were in the billions per year. For example, in 2008, it was among the top-10 drugs by revenue in the U.S. with sales exceeding US$2.4 billion. (Wikipedia)
Genericization
The first generic versions of Actos were approved in the U.S. on August 17, 2012. (Medscape)
Multiple manufacturers now supply generic pioglitazone tablets (15 mg, 30 mg, 45 mg) in the U.S. (Drugs.com)
Combination Products
Pioglitazone has been combined with other agents to broaden its therapeutic use; for example: • ACTOplus Met (pioglitazone + metformin) was approved by FDA on August 29, 2005. (Drugs.com) • Duetact (pioglitazone + glimepiride) approval came in the U.S. around 2006. (Wikipedia) • Oseni (pioglitazone + alogliptin) is another fixed-dose combination with FDA approval in 2013. (Drugs.com)
Safety, Regulatory Concerns, and Withdrawals / Market Limitations
Over time, safety concerns emerged, particularly regarding risks such as bladder cancer, heart failure, weight gain, edema, etc. Some markets (France, Germany) suspended or withdrew Actos in 2011 over cancer risk concerns. (Wikipedia)
Regulatory labeling was updated to reflect such risks. (Wikipedia)
Current Status
Pioglitazone remains an approved, generic drug in many countries, widely prescribed for type 2 diabetes as an insulin sensitizer. (Wikipedia)
It is no longer under brand-exclusive patent (in many markets), so generic competition has lowered price and broadened access. (Drugs.com)
It’s very interesting, the consistent male bias of favorable interventions, at least in lower life forms. In humans my bet is that rapamycin and estrogen will be the biggest levers for women. These other things might be hit or miss, but the decline in estrogen seems to set off the master cascade of decline for women and replenishing it seamlessly seems to set things right — even helps men. Rapamycin among the organism wide changes also seems to be an anti fibrotic and good at particularly rejuvenating ovaries so that it also delays the orchestrated obsolescence.
Pioglitazone (another TZD) is one of my all time favorite longevity compounds. It’s readily available and I shared about it quite a bit in the Facebook Rapamycin group. E.g. Pioglitazone
Cocoa is turning out to be a no brainer supplement for longevity. Because it has numerous human trials showing benefits now! Plus ITP life extension. Further reading Cocoa
Very nice writeup on pioglitazone, though notably lacking in one of the biggest concerns: increased incidence of bladder cancer, which is strongly correlated both dose and time dependent. I too have explored pioglitazone (Work In Progress) in this thread:
I also think it’s pretty important to look at combining use of pioglitazone and other drugs. Statins, which you mention, but also telmisartan which has several possible synergies while possibly alleviating some of the undesirable side effects, such as weight gain. Also, SGLT2i, such as empagliflozin which might reduce edema and perhaps lower the HF danger.
As always, healthy aging and life prolongation is complex and unlikely for any single drug to have optimal effectiveness alone. Instead, carefully calibrated polypharmacy is called for, adjusted depending on one’s particular phenotype.
Atm, I’m doing lipid lowering therapy (pitavastatin, bempedoic acid, ezetimibe), glucose control (empagliflozin), BP control (telmisartan), and soon low dose (7.5mg/day) pioglitazone. Epicatechin I’m hoping to cover through dietary sources, daily cacao and green tea. And of course, rapamycin - 6mg/1-week. To the degree that I could, I’ve explored the possible interactions of these various molecules, but naturally, it’s a continuing and never ceasing work in progress (WIP).
I’ve been on Rosuvastatin (2.5mg), Lisinopril 10mg, Aspirin 80mg. Added ezetimibe on and off (still trying to get used to it). Pio 7.5mg is great but I think I’m getting too much bone marrow supression these days (so I’m not on it).
I wonder about EGCG, also. It has been claimed to inhibit DYRK1A, one of the genes influencing the DREAM Network (so does EGCG result in an increase in DNA repair?), though I’m not sure the same is true of plain epicatechin.
The results from the ITP (Intervention Testing Program) can absolutely be seen as a strong signal that excessive insulin signaling (hyperinsulinemia) is a key accelerator of mammalian aging. This aligns very well with Dr. Ben Bikman’s reasoning and the broader scientific understanding of the insulin/IGF-1 signaling pathway in aging. Insulin levels can be seen as the canary in the coal mine.
ITP, some of us here and biogerontologists know that the Insulin/Insulin-like Growth Factor 1 Signaling pathway is one of the most evolutionarily conserved pathways regulating aging. Reduced signaling in this pathway is strongly associated with increased lifespan and healthspan in species from worms and flies to mice. And some say that, low insulin signals is strongly associated with increased lifespan and healthspan even in long lived humans.
Excessive signaling is associated with accelerated aging and age-related diseases.Insulin is Not the Enemy, Hyper-insulinemia Is. Insulin is an essential anabolic hormone. We need it to live. The problem is the chronic, excessive levels. The ITP provides strong correlative signal for this reasoning.
But these drugs (drugs for type 2 diabetes) have other proposed anti-aging effects, like effects on mitochondria, AMPK activation, that may be independent of insulin. Lower insulin likely contributes to these other beneficial effects. High insulin activates besides IGF also mTOR.
Other concentrations will need to be tested, but based on the available evidence, acarbose is the antidiabetic drug with the greatest impact on lifespan in mice and with fewer potentially harmful side effects.”
I have been eagerly awaiting the forskolin results, as I take it as part of my bone building regimen and I wanted reassurance that it isn’t negatively affecting my longevity, as there seem to be no previous experiments where mammals have been fed forskolin for their entire life. I got that reassurance, at least, but looking deeper, it seems they tested it at a relatively low concentration of 8ppm in the chow, which translates to a significantly lower dose than many people take. 8ppm translates to less than 1 mg/kg/day, yes? I take 100 mg/day. They state in the paper, “We note, however, that FSK increased median survival of males by ~ 8%, although this did not reach statistical significance. It is possible that testing FSK at other doses might produce more impressive effects.”
Not at all. These are very different drugs. Pioglitazone is an old drug well known to act through activating PPARgamma. Mitoglitazone does not activate PPARgamma at all (at least not directly and probably not indirectly either to a significant extent). The fact that they both share the glitazone nomenclature can be misleading because it is a reflection of their similar chemical structure rather than of their mechanism of action. Similar chemical structure does not mean similar mechanism of action however.
