WEBVTT 00:00:00.000 --> 00:00:01.820 Ever feel like understanding your medication 00:00:01.820 --> 00:00:05.320 is like, ugh, trying to decode another language? 00:00:05.440 --> 00:00:07.759 Yeah, it really can be sometimes. Well, today, 00:00:08.019 --> 00:00:10.800 we're hoping to hand you the Rosetta Stone for 00:00:10.800 --> 00:00:13.240 pioglitazone. It's a name you might have heard, 00:00:13.419 --> 00:00:16.260 especially if you or someone you know is managing 00:00:16.260 --> 00:00:18.719 type 2 diabetes. And you've shared just a wealth 00:00:18.719 --> 00:00:21.120 of information on pioglitazone with us. We've 00:00:21.120 --> 00:00:23.920 really... dug into it all. I mean, everything 00:00:23.920 --> 00:00:26.140 from how it actually works in your body, its 00:00:26.140 --> 00:00:28.760 journey through all the regulatory hoops, and 00:00:28.760 --> 00:00:31.280 even some, well, surprising real -world impacts 00:00:31.280 --> 00:00:33.960 it's had. Right. Our mission today, really just 00:00:33.960 --> 00:00:36.020 to give you the clear need -to -know insights, 00:00:36.640 --> 00:00:39.119 without all the overwhelming jargon, if we can 00:00:39.119 --> 00:00:42.500 help it. Exactly. We're about to do a deep dive 00:00:42.500 --> 00:00:45.740 into the, frankly, quite intriguing story of 00:00:45.740 --> 00:00:48.020 Pale Clitizone. You know, where did it come from? 00:00:48.079 --> 00:00:50.979 What's its main job inside your body? The science 00:00:50.979 --> 00:00:53.079 behind it will touch on things like pharmacokinetics 00:00:53.079 --> 00:00:55.159 and pharmacodynamics, how your body handles it 00:00:55.159 --> 00:00:58.579 and what it does. But we promise to make it understandable. 00:00:59.100 --> 00:01:01.420 We keep it clear. Yeah. How it's made, the rules 00:01:01.420 --> 00:01:03.619 and regs surrounding it, and even touch on its 00:01:03.619 --> 00:01:06.319 broader effects, like on the economy and, well, 00:01:06.780 --> 00:01:08.799 maybe even culturally to some extent. Definitely. 00:01:09.120 --> 00:01:12.159 Think of this as your personal guided tour through 00:01:12.159 --> 00:01:15.569 this really important medication. So let's start 00:01:15.569 --> 00:01:17.329 at the beginning. Where does this story kick 00:01:17.329 --> 00:01:20.609 off? OK, so the story of pioglitazone really, 00:01:20.650 --> 00:01:25.069 it starts back in 1982. Scientists at a company 00:01:25.069 --> 00:01:28.129 called Takeda discovered this compound, ciglitazone. 00:01:28.650 --> 00:01:31.469 Ciglitazone, OK. Now, what made ciglitazone stand 00:01:31.469 --> 00:01:34.230 out was that it was the first of a whole new 00:01:34.230 --> 00:01:37.689 class of drugs. They're called thiazolid indiones. 00:01:38.579 --> 00:01:41.099 TZDs for short. TZDs, right. I've heard that 00:01:41.099 --> 00:01:43.439 term. And what it did in animal models was lower 00:01:43.439 --> 00:01:45.680 blood sugar in a totally new way compared to 00:01:45.680 --> 00:01:48.840 the older drugs, like sulfonylureous. It didn't 00:01:48.840 --> 00:01:51.200 just force the body to pump out more insulin. 00:01:51.620 --> 00:01:53.719 Ah, okay. So that's the key difference then. 00:01:53.719 --> 00:01:55.560 Instead of just telling the pancreas, make more 00:01:55.560 --> 00:01:58.099 insulin, it was doing something else. Precisely. 00:01:58.239 --> 00:02:00.340 It was working on insulin resistance. Yeah. You 00:02:00.340 --> 00:02:02.099 know, think of it like your cells weren't listening 00:02:02.099 --> 00:02:04.159 properly to the insulin your body was making. 00:02:04.620 --> 00:02:06.859 Sclutazone helped make them, well, more receptive. 00:02:07.079 --> 00:02:09.360 Interesting. So it tackles the sensitivity issue. 00:02:10.060 --> 00:02:14.060 Exactly. Now, suclatazone itself, it never actually 00:02:14.060 --> 00:02:16.060 made it to market. There were some toxicity issues 00:02:16.060 --> 00:02:18.340 that popped up in studies. But it was still a 00:02:18.340 --> 00:02:20.759 pivotal moment. It proved this whole approach, 00:02:20.879 --> 00:02:23.139 targeting insulin sensitivity, could actually 00:02:23.139 --> 00:02:27.580 work. And that really sparked a race. Other big 00:02:27.580 --> 00:02:30.099 pharma companies like Senkio and Smithline Beecham 00:02:30.099 --> 00:02:32.740 jumped in trying to find better, safer versions 00:02:32.740 --> 00:02:36.419 in the same TZD family. So, sigilidazone was 00:02:36.419 --> 00:02:39.120 kind of the proof of concept, the spark that 00:02:39.120 --> 00:02:41.479 lit the fire for this whole area. That's a great 00:02:41.479 --> 00:02:43.060 way to put it. Yeah, it laid the groundwork. 00:02:43.139 --> 00:02:46.840 The search continued, and eventually a drug called 00:02:46.840 --> 00:02:49.599 triglitazone became the first TZD that actually 00:02:49.599 --> 00:02:52.280 reached patients. That was in 1997. Okay, so 00:02:52.280 --> 00:02:55.060 triglitazone got there first. It did. But its 00:02:55.060 --> 00:02:57.039 time on the market was, well, unfortunately, 00:02:57.080 --> 00:02:59.800 pretty short. It got recalled in 2000. Recalled? 00:02:59.800 --> 00:03:02.879 Why? Concerns about liver toxicity. Serious ones. 00:03:02.979 --> 00:03:05.310 Wow. Okay, that must have been a pretty significant 00:03:05.310 --> 00:03:07.530 step back then. Probably raised a lot of questions 00:03:07.530 --> 00:03:09.509 about the safety of this entire class of drugs, 00:03:09.610 --> 00:03:12.169 didn't it? Oh, absolutely. It was a major challenge. 00:03:12.750 --> 00:03:14.770 But, you know, the underlying science, the idea 00:03:14.770 --> 00:03:17.229 of improving insulin sensitivity, still seemed 00:03:17.229 --> 00:03:19.729 really promising. Researchers learned a lot from 00:03:19.729 --> 00:03:22.330 the problems with triglitazone. Right. And those 00:03:22.330 --> 00:03:24.909 development efforts continued, which ultimately 00:03:24.909 --> 00:03:27.750 led to the launch of pyaglitazone, offering another 00:03:27.750 --> 00:03:30.819 option within this TZD class. Okay, so that brings 00:03:30.819 --> 00:03:34.560 us to pioglitazone itself. Fast forward to today, 00:03:35.120 --> 00:03:37.419 what are the main situations where it's actually 00:03:37.419 --> 00:03:40.680 used in clinical practice? So pioglitazone is 00:03:40.680 --> 00:03:44.280 primarily indicated as what we call a second 00:03:44.280 --> 00:03:46.520 or third line treatment for type 2 diabetes in 00:03:46.520 --> 00:03:49.039 adults. It's often considered particularly for 00:03:49.039 --> 00:03:51.439 patients who are also overweight. Second or third 00:03:51.439 --> 00:03:53.620 line, meaning not usually the first thing doctors 00:03:53.620 --> 00:03:56.530 try. Generally, yes. It can be used as what's 00:03:56.530 --> 00:03:59.330 called monotherapy, meaning on its own, or more 00:03:59.330 --> 00:04:01.610 commonly perhaps, it's used in combination with 00:04:01.610 --> 00:04:03.930 other standard diabetes medications, things like 00:04:03.930 --> 00:04:07.289 Metformin, sulfonylureas, or even insulin. That's 00:04:07.289 --> 00:04:08.969 typically for people who aren't quite getting 00:04:08.969 --> 00:04:11.229 their blood sugar under control with their existing 00:04:11.229 --> 00:04:14.240 treatment plan. And I assume we have... solid 00:04:14.240 --> 00:04:16.100 evidence, like clinical trials, showing that 00:04:16.100 --> 00:04:18.639 it actually helps in those situations. Oh, absolutely. 00:04:19.100 --> 00:04:21.120 Numerous clinical trials have demonstrated that 00:04:21.120 --> 00:04:24.199 when you add pioglitazone to existing treatments, 00:04:24.279 --> 00:04:26.860 whether that's sulfonylureas, metformin, or insulin, 00:04:27.339 --> 00:04:31.860 it leads to statistically significant improvements 00:04:31.860 --> 00:04:34.300 in blood sugar control. How do they measure that 00:04:34.300 --> 00:04:37.100 improvement? They look at key markers, specifically 00:04:37.100 --> 00:04:39.980 HbA1c, which gives you that average picture of 00:04:39.980 --> 00:04:42.899 blood sugar levels over, say, the last three 00:04:42.899 --> 00:04:45.980 months or so. Right, the A1C test. Exactly. And 00:04:45.980 --> 00:04:48.860 also fasting plasma glucose, which is your blood 00:04:48.860 --> 00:04:50.339 trigger level first thing in the morning before 00:04:50.339 --> 00:04:53.420 you eat. Pyoglitazone helps bring both of those 00:04:53.420 --> 00:04:55.939 down. Now, you mentioned earlier its journey. 00:04:56.160 --> 00:04:58.439 I remember seeing information, maybe some controversy, 00:04:58.819 --> 00:05:01.220 about pyoglitazone and its effects on the heart 00:05:01.220 --> 00:05:04.319 and blood vessels. That's obviously a huge concern 00:05:04.319 --> 00:05:06.899 for people with type 2 diabetes. Yes, that is 00:05:06.899 --> 00:05:09.000 a really critical point, and it's something researchers 00:05:09.000 --> 00:05:11.220 look at very closely. There was a major study 00:05:11.220 --> 00:05:14.439 called the POACTIVE study. Proactive, okay. Yeah, 00:05:14.560 --> 00:05:16.839 it stands for Perspective Pyoglitazone Clinical 00:05:16.839 --> 00:05:19.680 Trial in Macrovascular Events. Quite a mouthful. 00:05:19.850 --> 00:05:22.649 Eh, sounds like it. But it's specifically designed 00:05:22.649 --> 00:05:24.889 to investigate this cardiovascular question. 00:05:25.490 --> 00:05:29.110 It involved I think over 5 ,000 people. All had 00:05:29.110 --> 00:05:32.750 type 2 diabetes and also a prior history of cardiovascular 00:05:32.750 --> 00:05:35.870 disease like a heart attack or stroke. So a high 00:05:35.870 --> 00:05:38.189 -risk group, what did they find? Well, it's a 00:05:38.189 --> 00:05:41.259 bit nuanced. The study's main goal, its primary 00:05:41.259 --> 00:05:43.379 endpoint, looked at a pretty broad combination 00:05:43.379 --> 00:05:45.680 of different cardiovascular events. And on that 00:05:45.680 --> 00:05:48.639 main goal, piaglitazone didn't show a statistically 00:05:48.639 --> 00:05:51.600 significant benefit across the board. Hmm, okay. 00:05:51.980 --> 00:05:54.199 So not a home run on the main target. Not on 00:05:54.199 --> 00:05:56.560 the primary one, no. But, and this is important, 00:05:56.879 --> 00:05:58.740 the researchers also looked at a more specific 00:05:58.740 --> 00:06:01.120 set of outcomes. This is called the main secondary 00:06:01.120 --> 00:06:03.300 endpoint. Okay, what did that include? It focused 00:06:03.300 --> 00:06:06.100 on the combination of death from any cause, a 00:06:06.100 --> 00:06:09.480 non -fatal heart attack, or MI myocardial infarction, 00:06:09.620 --> 00:06:12.480 or stroke. And for that specific combination, 00:06:12.720 --> 00:06:14.699 there was a statistically significant decrease 00:06:14.699 --> 00:06:17.519 seen in the patients taking piaglitazone. Oh, 00:06:17.519 --> 00:06:20.019 interesting. So even though it didn't hit that 00:06:20.019 --> 00:06:23.019 broad primary goal, it did seem to offer some 00:06:23.019 --> 00:06:25.839 protection against these really critical, hard 00:06:25.839 --> 00:06:27.800 endpoints. Exactly. That's how many interpreted 00:06:27.800 --> 00:06:31.019 it. And when they dug even deeper into the pre 00:06:31.019 --> 00:06:33.680 -oactive data in later analyses, things got even 00:06:33.680 --> 00:06:36.110 more interesting. How so? Well, some analyses 00:06:36.110 --> 00:06:39.490 suggested more specific benefits, like potentially 00:06:39.490 --> 00:06:41.389 reducing the risk of having a recurrent heart 00:06:41.389 --> 00:06:44.670 attack. And there were also hints of potential 00:06:44.670 --> 00:06:47.670 anti -arthrogenic effects, meaning slowing down 00:06:47.670 --> 00:06:49.949 the hardening of the arteries. Really? How would 00:06:49.949 --> 00:06:51.829 it do that? Well, for instance, another study 00:06:51.829 --> 00:06:54.730 called the Chicago study indicated it might reduce 00:06:54.730 --> 00:06:57.329 the thickness of the carotid artery wall that's 00:06:57.329 --> 00:06:59.850 a key artery in your neck, and thickening there 00:06:59.850 --> 00:07:02.740 is a sign of atherosclerosis. This effect might 00:07:02.740 --> 00:07:05.459 be linked possibly to pioglitazone's ability 00:07:05.459 --> 00:07:08.459 to increase levels of HDL cholesterol. The good 00:07:08.459 --> 00:07:11.220 cholesterol. That's the one, yeah. HDL is thought 00:07:11.220 --> 00:07:13.779 to help clear plaque from arteries. Okay. And 00:07:13.779 --> 00:07:16.060 what about stroke specifically? Any insights 00:07:16.060 --> 00:07:18.220 there? Yeah, another important trial called the 00:07:18.220 --> 00:07:21.180 IRS trial that's short for insulin resistance 00:07:21.180 --> 00:07:25.639 intervention. After stroke, looked at pioglitazone 00:07:25.639 --> 00:07:28.360 specifically in people who were insulin resistant. 00:07:29.160 --> 00:07:32.959 and had recently had either a stroke or a TIA, 00:07:33.560 --> 00:07:35.660 a transient ischemic attack, sometimes called 00:07:35.660 --> 00:07:38.720 a mini -stroke. Right. And that study suggested 00:07:38.720 --> 00:07:41.519 a potential benefit in lowering the risk of what 00:07:41.519 --> 00:07:44.639 they call MAVIS. major adverse cardiovascular 00:07:44.639 --> 00:07:47.220 events in patients who already had established 00:07:47.220 --> 00:07:50.040 cardiovascular disease. So quite a complex picture 00:07:50.040 --> 00:07:53.079 on the cardiovascular front, but with some definite 00:07:53.079 --> 00:07:55.459 signals of potential benefit, especially in certain 00:07:55.459 --> 00:07:57.699 high -risk groups. That's a fair summary, yes. 00:07:57.800 --> 00:07:59.819 Yeah. It's not straightforward, but there's evidence 00:07:59.819 --> 00:08:02.180 suggesting benefits beyond just blood sugar control. 00:08:02.339 --> 00:08:05.480 Okay. Now, besides its main job in diabetes and 00:08:05.480 --> 00:08:07.899 these potential cardiovascular effects, you mentioned 00:08:07.899 --> 00:08:09.879 it's being looked at for other things. Any other 00:08:09.879 --> 00:08:12.100 conditions where pyaglitazone is being invested? 00:08:11.920 --> 00:08:14.839 Yeah, there's actually ongoing research in several 00:08:14.839 --> 00:08:16.480 different areas, which is pretty interesting. 00:08:16.839 --> 00:08:18.699 Some studies, for example, have explored whether 00:08:18.699 --> 00:08:21.220 it might help improve symptoms of psoriasis, 00:08:21.500 --> 00:08:24.139 which is an inflammatory skin condition. Psoriasis, 00:08:24.160 --> 00:08:26.459 huh. OK. There's also been research in animal 00:08:26.459 --> 00:08:29.879 models, so very early stage suggesting it might 00:08:29.879 --> 00:08:32.100 potentially have a role in treating opioid use 00:08:32.100 --> 00:08:34.879 disorder. Yeah, that's unexpected. It is. And 00:08:34.879 --> 00:08:37.700 another area is Alzheimer's disease. Preclinical 00:08:37.700 --> 00:08:40.139 studies, again, mostly in labs and animals, look 00:08:40.139 --> 00:08:44.259 promising. But the clinical trials conducted 00:08:44.259 --> 00:08:47.399 in humans with Alzheimer's haven't really yielded 00:08:47.399 --> 00:08:50.549 conclusive results so far. The jury is still 00:08:50.549 --> 00:08:52.509 out on that one. It's really remarkable, though, 00:08:52.610 --> 00:08:55.029 isn't it, how a drug initially developed for 00:08:55.029 --> 00:08:58.450 one specific purpose, like diabetes, can show 00:08:58.450 --> 00:09:01.470 potential in such diverse areas. It really highlights 00:09:01.470 --> 00:09:04.090 how interconnected biological pathways can be. 00:09:04.309 --> 00:09:06.309 OK, so we've got a good handle now on what P 00:09:06.309 --> 00:09:08.750 -ogletazone is used for. But how does it actually 00:09:08.750 --> 00:09:11.350 work? What's going on inside the body at a cellular 00:09:11.350 --> 00:09:14.190 level? Right, the mechanism of action. So the 00:09:14.190 --> 00:09:16.629 primary way pioglitazone works is by activating 00:09:16.629 --> 00:09:19.090 a very specific type of receptor inside your 00:09:19.090 --> 00:09:21.690 cells. It's called the paroxysome proliferator 00:09:21.690 --> 00:09:24.330 activated receptor gamma. Let's just call it 00:09:24.330 --> 00:09:26.929 PPAR gamma. PPAR gamma. Got it. Rolls right off 00:09:26.929 --> 00:09:30.460 the tongue. Tuckles. Yeah. Not exactly. But think 00:09:30.460 --> 00:09:33.200 of PPAR -gamma as kind of like a master switch 00:09:33.200 --> 00:09:35.519 inside certain cells, particularly fat cells 00:09:35.519 --> 00:09:38.360 and muscle cells. When pioglitazone comes along 00:09:38.360 --> 00:09:40.820 and binds to it, it activates this switch. OK. 00:09:40.860 --> 00:09:43.200 It flips the PPAR -gamma switch. And what happens 00:09:43.200 --> 00:09:46.259 then? Well, PPAR -gamma doesn't work alone. It 00:09:46.259 --> 00:09:48.759 actually comes in two main forms, PPAR -gamma 00:09:48.759 --> 00:09:51.340 1 and 2. And it needs to partner up with another 00:09:51.340 --> 00:09:54.759 receptor called the retinoid X receptor, or RXR. 00:09:54.980 --> 00:09:57.960 They form a team. a heterodimer. OK, so PPAR, 00:09:58.059 --> 00:10:01.320 gamma, and RXR team up when pioglitazone is present. 00:10:01.480 --> 00:10:04.899 Exactly. And this activated team then goes and 00:10:04.899 --> 00:10:07.379 influences which genes inside the cell nucleus 00:10:07.379 --> 00:10:10.039 get turned on or off. It changes gene expression. 00:10:10.340 --> 00:10:12.700 And the result of those gene changes is? The 00:10:12.700 --> 00:10:15.000 ultimate result is improved insulin sensitivity. 00:10:15.820 --> 00:10:17.740 The muscle and fat tissues become much better 00:10:17.740 --> 00:10:19.659 at responding to insulin and taking up glucose 00:10:19.659 --> 00:10:21.970 from the bloodstream. It also dials down the 00:10:21.970 --> 00:10:24.009 amount of glucose being produced unnecessarily 00:10:24.009 --> 00:10:26.350 by the liver. So it's tackling those core issues 00:10:26.350 --> 00:10:28.990 in type 2 diabetes, the cells ignoring insulin, 00:10:29.490 --> 00:10:31.129 and the liver making too much sugar right at 00:10:31.129 --> 00:10:33.169 the genetic level almost. That's a good way to 00:10:33.169 --> 00:10:35.330 think about it, yeah. It's reprogramming the 00:10:35.330 --> 00:10:37.350 cells to be more insulin sensitive. And does 00:10:37.350 --> 00:10:39.509 it do anything else besides affecting glucose? 00:10:39.669 --> 00:10:43.789 Yes it does. Activating PPAR gamma also has significant 00:10:43.789 --> 00:10:46.879 effects on how your body handles fats. or lipids. 00:10:47.379 --> 00:10:49.820 It often leads to a decrease in triglycerides 00:10:49.820 --> 00:10:52.559 that's a type of fat in your blood. Right. And, 00:10:52.720 --> 00:10:55.220 as we mentioned earlier, it often increases HDLC, 00:10:55.379 --> 00:10:58.139 that good cholesterol. Okay, so effects on both 00:10:58.139 --> 00:11:01.059 sugar and fats. And potentially one more thing. 00:11:01.600 --> 00:11:03.740 It might also modify the secretion of certain 00:11:03.740 --> 00:11:06.659 hormones produced by fat tissue itself. These 00:11:06.659 --> 00:11:10.639 are called adipokines. And changes in these adipokines 00:11:10.639 --> 00:11:13.139 can further contribute to improved insulin sensitivity 00:11:13.139 --> 00:11:15.360 throughout the body. Fascinating. It's clearly 00:11:15.360 --> 00:11:17.240 doing a lot more than just one simple thing. 00:11:17.419 --> 00:11:19.539 Definitely a multifaceted mechanism. Okay, that 00:11:19.539 --> 00:11:21.580 gives us a much clearer picture of how it works. 00:11:21.879 --> 00:11:23.620 Now let's talk about the journey of the drug 00:11:23.620 --> 00:11:26.759 through the body. You take a pioglitazone tablet. 00:11:27.279 --> 00:11:31.019 What happens next? The pharmacokinetics. Right. 00:11:31.460 --> 00:11:33.820 So actually you take it orally. Pioglitazone 00:11:33.820 --> 00:11:36.509 gets absorbed into your bloodstream. pretty reliably. 00:11:37.070 --> 00:11:38.809 It usually reaches its highest concentration, 00:11:39.029 --> 00:11:41.730 its peak level, within about two hours. Does 00:11:41.730 --> 00:11:44.350 taking it with food make a difference? It can 00:11:44.350 --> 00:11:46.509 slow down the absorption a bit. That peak time 00:11:46.509 --> 00:11:48.309 might get delayed to maybe three or four hours 00:11:48.309 --> 00:11:50.830 if you take it with a meal. But, and this is 00:11:50.830 --> 00:11:53.549 key, the total amount of the drug that actually 00:11:53.549 --> 00:11:55.710 gets absorbed into your system, what you call 00:11:55.710 --> 00:11:59.250 the AUC or area under the curve, isn't significantly 00:11:59.250 --> 00:12:02.139 affected by food. OK, so it still all gets in 00:12:02.139 --> 00:12:04.360 eventually, just maybe a bit slower with food. 00:12:04.820 --> 00:12:07.019 Once it's in the bloodstream, where does it go? 00:12:07.100 --> 00:12:09.440 Does it spread out evenly? It distributes quite 00:12:09.440 --> 00:12:11.840 well throughout the body. We measure this using 00:12:11.840 --> 00:12:14.019 something called the apparent volume of distribution. 00:12:14.279 --> 00:12:17.419 And for pyoglitazone, it's around 0 .63 liters 00:12:17.419 --> 00:12:20.480 per kilogram of body weight, which suggests decent 00:12:20.480 --> 00:12:22.980 tissue penetration. Another important point is 00:12:22.980 --> 00:12:25.639 that it's very highly bound to proteins in your 00:12:25.639 --> 00:12:27.840 blood plasma. Protein bound. What does that mean? 00:12:28.029 --> 00:12:30.590 It means that most of the drug molecules circulating 00:12:30.590 --> 00:12:33.370 in your blood aren't free. They're attached, 00:12:33.629 --> 00:12:37.450 mostly to a protein called albumin. Over 99 % 00:12:37.450 --> 00:12:40.019 of PL glutazone is bound like this. Does that 00:12:40.019 --> 00:12:42.419 affect how it works? It affects how much free 00:12:42.419 --> 00:12:44.460 drug is available to actually get into tissues 00:12:44.460 --> 00:12:47.559 and activate those PPA or gamma receptors. It 00:12:47.559 --> 00:12:49.779 also influences how long it stays in the body 00:12:49.779 --> 00:12:52.320 and how it's eliminated. Interestingly, the active 00:12:52.320 --> 00:12:54.960 forms that pioglitazone gets converted into are 00:12:54.960 --> 00:12:57.799 also highly protein bound. Ah, active forms. 00:12:58.019 --> 00:13:00.299 So the body doesn't just use pioglitazone as 00:13:00.299 --> 00:13:01.980 is, it breaks it down into other things that 00:13:01.980 --> 00:13:04.279 also work. That's exactly right. Pioglitazone 00:13:04.279 --> 00:13:06.919 undergoes quite extensive metabolism. Primarily 00:13:06.919 --> 00:13:08.980 in the liver, it gets processed through chemical 00:13:08.980 --> 00:13:11.299 reactions called hydroxylation and oxidation. 00:13:11.600 --> 00:13:14.320 And specific enzymes do that job. Yes. The main 00:13:14.320 --> 00:13:17.279 enzyme responsible is called CYP2C8. Another 00:13:17.279 --> 00:13:20.899 one, CYP3A4, plays a lesser role. These enzymes 00:13:20.899 --> 00:13:23.059 convert pyaglitazone into active metabolites. 00:13:23.120 --> 00:13:24.840 The most important ones are known as M -I -T 00:13:24.840 --> 00:13:27.759 and M -I -V. So these M -I -T and M -I -V metabolites 00:13:27.759 --> 00:13:29.980 also contribute to the drug's effect. They do. 00:13:30.139 --> 00:13:33.600 They are also active PPAR gamma agonists. And 00:13:33.600 --> 00:13:35.899 then these metabolites undergo further processing 00:13:35.899 --> 00:13:39.179 called conjugation. They get tagged with glucuronide 00:13:39.179 --> 00:13:41.620 or sulfate molecules, which generally makes them 00:13:41.620 --> 00:13:44.419 easier to excrete. OK, so how long do pioglitazone 00:13:44.419 --> 00:13:46.720 and these active metabolites actually stick around 00:13:46.720 --> 00:13:49.419 in the body? What's the half life? The original 00:13:49.419 --> 00:13:52.000 pioglitazone molecule itself actually has a fairly 00:13:52.000 --> 00:13:54.899 short half life in the blood serum, typically 00:13:54.899 --> 00:13:57.000 somewhere between three and seven hours. That 00:13:57.000 --> 00:13:59.120 seems quite short for a drug often taken once 00:13:59.120 --> 00:14:02.200 a day. It does, but remember those active metabolites, 00:14:02.399 --> 00:14:05.879 M3 and MIV, they have much longer half -lives, 00:14:06.080 --> 00:14:08.600 somewhere in the range of 16 to 24 hours. Ah, 00:14:08.759 --> 00:14:11.159 okay. So even after the original drug levels 00:14:11.159 --> 00:14:13.779 drop, these active metabolites hang around much 00:14:13.779 --> 00:14:16.179 longer, continuing the effect. Precisely. Their 00:14:16.179 --> 00:14:18.820 longer duration is a key reason why puoglinozone 00:14:18.820 --> 00:14:21.899 can often be dosed just once daily. Makes sense. 00:14:22.419 --> 00:14:24.919 And how does the body finally get rid of pioglitazone 00:14:24.919 --> 00:14:27.740 and all its byproducts? Elimination? Well, a 00:14:27.740 --> 00:14:29.659 portion of it, maybe around 15 to 30 percent 00:14:29.659 --> 00:14:31.580 of the original dose, is eventually recovered 00:14:31.580 --> 00:14:33.700 in the urine, but mostly in the form of those 00:14:33.700 --> 00:14:36.600 metabolites, not the original drug. So not primarily 00:14:36.600 --> 00:14:39.440 through the kidneys, then? It seems not. The 00:14:39.440 --> 00:14:42.039 presumed major route of elimination is actually 00:14:42.039 --> 00:14:44.860 through the bile. produced by the liver, which 00:14:44.860 --> 00:14:47.600 then gets excreted into the digestive tract and 00:14:47.600 --> 00:14:49.679 ultimately leaves the body and the feces. Okay, 00:14:49.759 --> 00:14:52.600 interesting. What about people whose organs aren't 00:14:52.600 --> 00:14:55.360 working perfectly? Say someone with kidney problems 00:14:55.360 --> 00:14:58.460 or liver issues. Does that change how their body 00:14:58.460 --> 00:15:01.320 handles pioglitazone? That's a really important 00:15:01.320 --> 00:15:03.960 practical question. Interestingly, for kidney 00:15:03.960 --> 00:15:06.740 impairment, even moderate or severe kidney disease, 00:15:07.500 --> 00:15:10.039 the half -life of pioglitazone and its active 00:15:10.039 --> 00:15:12.379 metabolites doesn't seem to change significantly. 00:15:12.799 --> 00:15:15.200 So no dose adjustment needed for kidney patients? 00:15:15.419 --> 00:15:17.539 Generally, no dose adjustments are recommended 00:15:17.539 --> 00:15:20.960 based on kidney function alone. Now for the liver, 00:15:21.200 --> 00:15:23.559 it's a bit different. For mild to moderate liver 00:15:23.559 --> 00:15:25.840 impairment, dose adjustments usually aren't required 00:15:25.840 --> 00:15:28.120 either, but doctors are advised to use caution. 00:15:28.360 --> 00:15:31.580 But what about more severe liver problems? Yeah, 00:15:31.580 --> 00:15:33.960 that's where you have to be careful. Starting 00:15:33.960 --> 00:15:36.700 paleoglitazone is actually contraindicated, meaning 00:15:36.700 --> 00:15:38.480 it shouldn't be done in patients who have active 00:15:38.480 --> 00:15:41.419 liver disease. Or if their liver enzyme levels, 00:15:41.659 --> 00:15:44.340 specifically ALT, are significantly elevated, 00:15:44.399 --> 00:15:47.279 say more than 2 .5 times the upper limit of what's 00:15:47.279 --> 00:15:49.440 considered normal. And monitoring is needed. 00:15:49.679 --> 00:15:51.879 Absolutely. Liver function tests should be monitored 00:15:51.879 --> 00:15:54.460 periodically during treatment. And if those ALT 00:15:54.460 --> 00:15:57.340 levels climb too high, say over three times the 00:15:57.340 --> 00:16:00.269 normal limit? or if the patient develops jaundice, 00:16:00.529 --> 00:16:02.509 yellowing of the skin or eyes, the drug should 00:16:02.509 --> 00:16:04.679 be stopped. Okay, so liver health is definitely 00:16:04.679 --> 00:16:07.419 a key consideration. Are there any significant 00:16:07.419 --> 00:16:09.519 interactions with other medications people should 00:16:09.519 --> 00:16:13.399 be aware of? Drug interactions? Yes. Since pyaglitazone 00:16:13.399 --> 00:16:16.460 is primarily broken down by that CYP2C8 enzyme, 00:16:17.059 --> 00:16:20.039 other drugs that affect CYP2C8 can be an issue. 00:16:20.360 --> 00:16:23.659 Oh, so? Well, drugs that inhibit CYP2C8 can slow 00:16:23.659 --> 00:16:26.139 down the metabolism of pyaglitazone, potentially 00:16:26.139 --> 00:16:28.789 leading to higher levels of it in the body. A 00:16:28.789 --> 00:16:31.090 classic example is Gemfibrozil, which is a drug 00:16:31.090 --> 00:16:33.429 used to lower cholesterol and triglycerides. 00:16:33.830 --> 00:16:36.850 Taking Gemfibrozil with pioglitazone can significantly 00:16:36.850 --> 00:16:39.549 increase pioglitazone exposure. So doctors need 00:16:39.549 --> 00:16:42.629 to be aware of that combination. Does pioglitazone 00:16:42.629 --> 00:16:45.309 itself affect other drugs? Based on studies, 00:16:45.529 --> 00:16:48.230 pioglitazone doesn't appear to be a strong inducer 00:16:48.230 --> 00:16:52.990 or inhibitor of other major CYP enzymes. So it's 00:16:52.990 --> 00:16:55.649 less likely to significantly mess with the levels 00:16:55.649 --> 00:16:58.220 of many other common medications. Okay. And just 00:16:58.220 --> 00:17:00.700 to recap the pharmacodynamics, how it affects 00:17:00.700 --> 00:17:04.210 the body. The key point is improving insulin 00:17:04.210 --> 00:17:06.470 sensitivity, right? Not making more insulin. 00:17:06.730 --> 00:17:09.289 Exactly. That's its core pharmacodynamic effect. 00:17:09.329 --> 00:17:11.990 It makes your existing insulin work better without 00:17:11.990 --> 00:17:14.250 directly stimulating the pancreas to release 00:17:14.250 --> 00:17:17.069 more. That distinguishes it from some other classes 00:17:17.069 --> 00:17:19.990 of diabetes drugs. Got it. OK, we've covered 00:17:19.990 --> 00:17:22.210 how it works and how the body handles it. Let's 00:17:22.210 --> 00:17:24.349 switch gears now to how it's actually made, the 00:17:24.349 --> 00:17:27.349 manufacturing process. What goes into creating 00:17:27.349 --> 00:17:30.049 pioglitazone tablets? Sure. The synthesis of 00:17:30.049 --> 00:17:32.339 drugs in the phyazole in the deuna family, like 00:17:32.339 --> 00:17:34.740 piaglitazone, usually involves a series of chemical 00:17:34.740 --> 00:17:37.400 reactions. Often they start with relatively simple 00:17:37.400 --> 00:17:39.420 chemical building blocks, things like thuria 00:17:39.420 --> 00:17:42.319 and chloroacetic acid. OK, basic chemicals. Right. 00:17:42.880 --> 00:17:45.180 These react to form an intermediate structure, 00:17:45.359 --> 00:17:48.119 kind of a core ring structure called 2 -mnO4 00:17:48.119 --> 00:17:50.900 -thizalitinone. This then serves as the foundation. 00:17:51.519 --> 00:17:53.440 And further chemical modifications are made to 00:17:53.440 --> 00:17:56.180 build the specific piaglitazone molecule with 00:17:56.180 --> 00:17:59.160 its unique side chains. Is this like old -school 00:17:59.160 --> 00:18:02.359 chemistry or are there modern improvements to 00:18:02.359 --> 00:18:05.799 the process? Well, like in many areas of pharmaceutical 00:18:05.799 --> 00:18:07.680 manufacturing, there's definitely a push towards 00:18:07.680 --> 00:18:10.599 developing greener and more efficient synthesis 00:18:10.599 --> 00:18:13.680 methods. Greener how? For instance, researchers 00:18:13.680 --> 00:18:16.140 have explored using things like microwave energy 00:18:16.140 --> 00:18:18.339 to help drive some of the chemical reactions. 00:18:18.839 --> 00:18:21.180 This can often dramatically reduce the reaction 00:18:21.180 --> 00:18:23.740 times needed and lower the temperatures required, 00:18:24.000 --> 00:18:26.079 which saves energy and can potentially reduce 00:18:26.079 --> 00:18:28.599 waste. That's good to hear. So once the basic 00:18:28.599 --> 00:18:30.980 pioglitazone molecule is synthesized, what's 00:18:30.980 --> 00:18:33.500 next? After the core structure is built, there 00:18:33.500 --> 00:18:35.839 are usually additional steps to attach specific 00:18:35.839 --> 00:18:38.200 chemical groups onto it at very precise locations. 00:18:38.500 --> 00:18:41.099 This might involve reactions like something called 00:18:41.099 --> 00:18:43.640 novenageral condensation to add certain functional 00:18:43.640 --> 00:18:46.359 parts. Sounds complex. It involves careful control. 00:18:47.339 --> 00:18:50.160 Then, crucially, the synthesized pioglitazone 00:18:50.160 --> 00:18:52.680 needs to be purified to meet incredibly strict 00:18:52.680 --> 00:18:55.480 quality impurity standards set by regulatory 00:18:55.480 --> 00:18:58.440 agencies. Right. Can't have impurities. Exactly. 00:18:59.000 --> 00:19:01.240 And finally, the pure active drug substance is 00:19:01.240 --> 00:19:03.680 formulated into the final dosage form, usually 00:19:03.680 --> 00:19:06.680 tablets. This involves mixing the piaglitazone 00:19:06.680 --> 00:19:09.480 with various inactive ingredients called excipients. 00:19:09.900 --> 00:19:11.980 Excipients? What do they do? They serve many 00:19:11.980 --> 00:19:14.180 purposes. They help bind the tablet together, 00:19:14.640 --> 00:19:16.359 control how quickly it dissolves in your stomach 00:19:16.359 --> 00:19:19.779 or intestine, ensure stability over time, maybe 00:19:19.779 --> 00:19:22.150 affect the color or coating. They're essential 00:19:22.150 --> 00:19:24.710 for making a functional, stable pill. And what 00:19:24.710 --> 00:19:27.349 about generic versions? We see pioglitazone from 00:19:27.349 --> 00:19:29.910 different companies now. Yes. When the patents 00:19:29.910 --> 00:19:32.910 on the original brand name drug, Actos, expired, 00:19:33.490 --> 00:19:35.410 other companies could start making generic versions, 00:19:35.730 --> 00:19:38.289 like pioglitazone Activis or pioglitazone Curca 00:19:38.289 --> 00:19:40.609 you might see in Europe, or various generics 00:19:40.609 --> 00:19:42.289 in the US. Do they have to make it the exact 00:19:42.289 --> 00:19:45.180 same way? Not necessarily the exact same process, 00:19:45.660 --> 00:19:48.339 but they absolutely must demonstrate to regulators 00:19:48.339 --> 00:19:51.700 through rigorous testing that their generic product 00:19:51.700 --> 00:19:55.059 is bioequivalent to the original. Bioequivalent 00:19:55.059 --> 00:19:57.779 meaning? Meaning it gets absorbed into the bloodstream 00:19:57.779 --> 00:20:00.339 at the same rate and to the same extent as the 00:20:00.339 --> 00:20:02.720 brand name drug. Essentially, it delivers the 00:20:02.720 --> 00:20:05.059 same amount of active ingredient to your body 00:20:05.059 --> 00:20:07.599 in the same way. ensuring it should work just 00:20:07.599 --> 00:20:09.480 as effectively and safely. That makes sense. 00:20:09.579 --> 00:20:11.680 It ensures people get consistent treatment, whether 00:20:11.680 --> 00:20:15.019 it's brand or generic. Okay, now let's move into 00:20:15.019 --> 00:20:16.740 maybe the more controversial part of the story. 00:20:17.480 --> 00:20:19.799 The regulatory trajectory and the legal issues 00:20:19.799 --> 00:20:22.640 surrounding pioglitazone. When did it first get 00:20:22.640 --> 00:20:25.819 approved? So, Pioglitazone, marketed as Actos, 00:20:26.259 --> 00:20:28.140 first received its authorization for use in the 00:20:28.140 --> 00:20:31.039 European Union back in October 2000. The U .S. 00:20:31.240 --> 00:20:32.720 approval was around the same time, I believe 00:20:32.720 --> 00:20:35.720 1999. Okay, so early 2000s. And you mentioned 00:20:35.720 --> 00:20:38.000 controversy. I assume that relates mainly to 00:20:38.000 --> 00:20:40.400 the safety concerns we touched on earlier. Yes, 00:20:40.599 --> 00:20:44.019 primarily. Its regulatory journey since then 00:20:44.019 --> 00:20:46.380 has really been marked by significant scrutiny. 00:20:46.599 --> 00:20:49.079 especially regarding that potential association 00:20:49.079 --> 00:20:51.460 with an increased risk of bladder cancer. Why 00:20:51.460 --> 00:20:53.500 the bladder cancer link? That became a really 00:20:53.500 --> 00:20:56.319 big deal, didn't it? It absolutely did. The challenge 00:20:56.319 --> 00:20:58.779 was that findings from different studies, mostly 00:20:58.779 --> 00:21:01.099 observational studies looking back at patient 00:21:01.099 --> 00:21:04.579 records, weren't entirely consistent. How so? 00:21:04.900 --> 00:21:07.500 Some studies seem to show a statistically significant 00:21:07.500 --> 00:21:10.220 increased risk, maybe particularly with longer 00:21:10.220 --> 00:21:13.240 use or higher doses. But other studies didn't 00:21:13.240 --> 00:21:16.640 find a clear link. This inconsistency, this lack 00:21:16.640 --> 00:21:19.079 of a completely clear consensus, made things 00:21:19.079 --> 00:21:22.019 very difficult for regulators. So conflicting 00:21:22.019 --> 00:21:24.519 signals from the research. How did regulatory 00:21:24.519 --> 00:21:28.019 agencies react to that uncertainty? Well, it 00:21:28.019 --> 00:21:31.079 led to significant action. In 2011, things really 00:21:31.079 --> 00:21:33.279 came to a head. Both France and Germany took 00:21:33.279 --> 00:21:36.220 the step of actually suspending the use of pioglitazone 00:21:36.220 --> 00:21:38.500 within their countries as a precautionary measure, 00:21:39.019 --> 00:21:41.259 based on the data they reviewed. Wow, suspension. 00:21:41.460 --> 00:21:44.240 That's serious. It was. The European Medicines 00:21:44.240 --> 00:21:47.259 Agency, the EMA, conducted its own comprehensive 00:21:47.259 --> 00:21:49.980 review of all the available evidence and ended 00:21:49.980 --> 00:21:52.759 up issuing updated recommendations, basically 00:21:52.759 --> 00:21:55.420 tightening the conditions for its use and emphasizing 00:21:55.420 --> 00:21:57.859 the need to weigh risks and benefits carefully. 00:21:58.059 --> 00:22:00.900 And what about the FDA in the U .S.? The FDA 00:22:00.900 --> 00:22:03.680 also took action. They updated the drug labels 00:22:03.680 --> 00:22:06.519 for pialglinezone to include much stronger warnings 00:22:06.519 --> 00:22:09.450 about the potential risk of bladder cancer. The 00:22:09.450 --> 00:22:11.930 advice became to avoid using it in patients who 00:22:11.930 --> 00:22:14.349 currently had active bladder cancer and to use 00:22:14.349 --> 00:22:17.569 it only with extreme caution after careful consideration 00:22:17.569 --> 00:22:20.410 of benefits versus risks in anyone with a prior 00:22:20.410 --> 00:22:23.089 history of bladder cancer. So heightened warnings 00:22:23.089 --> 00:22:25.289 and restrictions on use. This must have also 00:22:25.289 --> 00:22:27.210 triggered legal action from patients, right? 00:22:27.250 --> 00:22:29.190 People who developed bladder cancer after taking 00:22:29.190 --> 00:22:31.869 the drug. Yes, inevitably. Thousands upon thousands 00:22:31.869 --> 00:22:34.430 of lawsuits were filed against Takeda, the manufacturer 00:22:34.430 --> 00:22:37.319 of Actos. Eli Lilly was also involved initially 00:22:37.319 --> 00:22:39.859 in the U .S. marketing and faced lawsuits too. 00:22:40.119 --> 00:22:41.740 What were the main claims in these lawsuits? 00:22:42.200 --> 00:22:44.839 The core allegation was that the companies knew 00:22:44.839 --> 00:22:47.039 or should have known about the potential link 00:22:47.039 --> 00:22:49.759 between actus use and bladder cancer and that 00:22:49.759 --> 00:22:52.059 they failed to provide adequate warnings about 00:22:52.059 --> 00:22:55.500 this risk to both patients and doctors in a timely 00:22:55.500 --> 00:22:57.980 manner. And did these lawsuits go anywhere? Oh 00:22:57.980 --> 00:23:01.319 yes. They had a huge impact. Many of the federal 00:23:01.319 --> 00:23:03.519 cases in the U .S. were consolidated into what's 00:23:03.519 --> 00:23:07.039 called a multi -district litigation or MDL to 00:23:07.039 --> 00:23:09.640 manage them more efficiently. Some of the early 00:23:09.640 --> 00:23:12.539 Bellwether trials test cases essentially resulted 00:23:12.539 --> 00:23:15.079 in very large jury verdicts for the plaintiffs. 00:23:15.400 --> 00:23:17.339 I think I remember hearing about one massive 00:23:17.339 --> 00:23:19.740 verdict. They probably did. There was one particularly 00:23:19.740 --> 00:23:22.500 notable case where the jury awarded an absolutely 00:23:22.500 --> 00:23:25.539 staggering nine billion dollars in punitive damages. 00:23:26.329 --> 00:23:28.289 Now that amount was later significantly reduced 00:23:28.289 --> 00:23:30.670 by the judge, as often happens, but it certainly 00:23:30.670 --> 00:23:32.630 sent shockwaves. Nine billion, even reduced. 00:23:32.690 --> 00:23:34.990 That's incredible. How did it all end? Well, 00:23:35.269 --> 00:23:37.190 facing potentially thousands more trials and 00:23:37.190 --> 00:23:39.789 uncertain outcomes, Takeda eventually decided 00:23:39.789 --> 00:23:42.950 to pursue a global settlement. In 2015, they 00:23:42.950 --> 00:23:44.789 reached an agreement to pay approximately $2 00:23:44.789 --> 00:23:48.230 .4 billion to resolve the vast majority of these 00:23:48.230 --> 00:23:51.609 Actos bladder cancer lawsuits. $2 .4 billion. 00:23:52.430 --> 00:23:55.559 Still a massive amount. Absolutely. It's important 00:23:55.559 --> 00:23:58.440 to note, though, that as is common in these types 00:23:58.440 --> 00:24:00.980 of mass tort settlements, Takeda did not admit 00:24:00.980 --> 00:24:03.839 any liability or wrongdoing as part of the agreement. 00:24:04.519 --> 00:24:06.079 And were there conditions for patients to be 00:24:06.079 --> 00:24:08.619 part of that settlement? Yes. Generally, to be 00:24:08.619 --> 00:24:11.440 eligible, individuals needed to have been diagnosed 00:24:11.440 --> 00:24:14.380 with bladder cancer. And crucially, they usually 00:24:14.380 --> 00:24:16.700 had to have started taking Actos before the label 00:24:16.700 --> 00:24:19.359 was updated with the stronger warnings in December 00:24:19.359 --> 00:24:22.640 2011. The argument being that after that date, 00:24:22.799 --> 00:24:25.119 the risk information was more readily available. 00:24:25.400 --> 00:24:27.980 Okay, a really complex and significant legal 00:24:27.980 --> 00:24:31.400 saga for this drug. Now, beyond the bladder cancer 00:24:31.400 --> 00:24:34.099 issue, were there other safety concerns that 00:24:34.099 --> 00:24:36.559 regulators flagged or included in warnings? Yes, 00:24:36.700 --> 00:24:38.480 definitely. Bladder cancer got the most headlines. 00:24:39.059 --> 00:24:41.180 But pioglitazone has been associated with other 00:24:41.180 --> 00:24:43.779 important potential side effects, too. One quite 00:24:43.779 --> 00:24:46.500 common one is edema, which is fluid retention 00:24:46.500 --> 00:24:50.279 or swelling. Edema. Is that serious? It can be. 00:24:50.359 --> 00:24:52.500 especially because it seems to be dose -related 00:24:52.500 --> 00:24:55.579 more likely at higher doses. And this fluid retention 00:24:55.579 --> 00:24:59.059 can worsen existing heart failure or even contribute 00:24:59.059 --> 00:25:01.859 to new cases of congestive heart failure in people 00:25:01.859 --> 00:25:04.660 who are susceptible. Ah, so that links to heart 00:25:04.660 --> 00:25:07.480 health, too. Exactly. And because of that risk, 00:25:07.779 --> 00:25:10.059 pediatric zone is actually contraindicated again, 00:25:10.420 --> 00:25:12.519 shouldn't be used in patients who have more severe 00:25:12.519 --> 00:25:15.380 stages of heart failure, what's known as NYHA 00:25:15.380 --> 00:25:20.000 class 3 or 4 heart failure. OK. Any other major 00:25:20.000 --> 00:25:22.519 concerns? Another one that emerged is an increased 00:25:22.519 --> 00:25:25.380 risk of bone fractures. This seemed particularly 00:25:25.380 --> 00:25:28.839 noticeable in women and tended to involve nonvertebral 00:25:28.839 --> 00:25:31.359 fractures, so fractures in the arms, legs, hands, 00:25:31.400 --> 00:25:34.720 feet, rather than the spine. Fractures? Huh. 00:25:34.819 --> 00:25:36.920 That seems unexpected for a diabetes drug. It 00:25:36.920 --> 00:25:39.079 was somewhat unexpected, yes. And one more thing 00:25:39.079 --> 00:25:41.480 to mention is a potential, though less common, 00:25:41.640 --> 00:25:44.099 risk of developing macular edema. That swelling 00:25:44.099 --> 00:25:45.779 in the back of the eye that can affect vision. 00:25:46.259 --> 00:25:48.259 So any vision changes should be reported to a 00:25:48.259 --> 00:25:51.500 doctor. Wow. So bladder cancer, fluid retention, 00:25:52.119 --> 00:25:54.660 heart failure risk, fractures, potential eye 00:25:54.660 --> 00:25:57.720 issues. It really underscores the need for careful 00:25:57.720 --> 00:25:59.839 patient selection and monitoring, doesn't it? 00:26:00.160 --> 00:26:02.779 Absolutely. It's definitely a medication where 00:26:02.779 --> 00:26:05.039 the potential benefits for blood sugar control 00:26:05.039 --> 00:26:08.099 have to be very carefully weighed against this 00:26:08.099 --> 00:26:10.740 range of possible risks for each individual patient. 00:26:11.160 --> 00:26:13.220 Open communication between doctor and patient 00:26:13.220 --> 00:26:15.960 is key. You mentioned earlier how France and 00:26:15.960 --> 00:26:18.160 Germany suspended it. What about other parts 00:26:18.160 --> 00:26:20.200 of the world? Did regulations differ elsewhere? 00:26:20.299 --> 00:26:23.000 You mentioned India briefly. Right. India is 00:26:23.000 --> 00:26:25.519 an interesting case study in how different regulatory 00:26:25.519 --> 00:26:27.759 systems can sometimes arrive at different conclusions 00:26:27.759 --> 00:26:30.779 or at least take different actions. Pyoglitazone 00:26:30.779 --> 00:26:33.119 was, believe it or not, briefly banned in India 00:26:33.119 --> 00:26:35.779 at one point. Banned entirely. Yes. But that 00:26:35.779 --> 00:26:38.140 ban was later revoked. Part of the discussion 00:26:38.140 --> 00:26:40.019 there involved some studies conducted within 00:26:40.019 --> 00:26:42.519 India. These studies suggested that perhaps because 00:26:42.519 --> 00:26:44.660 the average doses used in India might be lower, 00:26:44.940 --> 00:26:47.140 or maybe because the baseline incidence of bladder 00:26:47.140 --> 00:26:49.420 cancer in the population is different, or maybe 00:26:49.420 --> 00:26:51.579 just due to limitations like smaller sample sizes 00:26:51.579 --> 00:26:54.720 in some studies. Right. The association between 00:26:54.720 --> 00:26:57.119 pyaglitazone and bladder cancer wasn't found 00:26:57.119 --> 00:26:59.519 to be statistically significant in some of those 00:26:59.519 --> 00:27:02.480 specific Indian studies. So the regulatory stance 00:27:02.480 --> 00:27:04.660 there evolved differently than in Europe or the 00:27:04.660 --> 00:27:07.500 US. Fascinating. It really shows how complex 00:27:07.500 --> 00:27:10.640 drug regulation can be on a global scale. OK, 00:27:11.059 --> 00:27:13.500 let's shift gears again and talk about the money 00:27:13.500 --> 00:27:16.440 side of things, the economic impact of pioglitazone. 00:27:16.619 --> 00:27:18.460 It's been around a while, generics are available. 00:27:18.740 --> 00:27:21.460 Yes, the market for pioglitazone has been, and 00:27:21.460 --> 00:27:24.460 likely still is, quite significant. That's driven 00:27:24.460 --> 00:27:26.660 simply by the sheer number of people living with 00:27:26.660 --> 00:27:29.759 type 2 diabetes around the world. A huge potential 00:27:29.759 --> 00:27:32.799 patient base. Exactly. And that market includes 00:27:32.799 --> 00:27:35.420 not just the original brand, Actos, but now all 00:27:35.420 --> 00:27:38.180 the various generic versions, plus combination 00:27:38.180 --> 00:27:40.960 pills that include pioglitazone alongside other 00:27:40.960 --> 00:27:43.480 drugs like metformin, pioglitazone combinations, 00:27:43.559 --> 00:27:45.640 which are quite common. Has the arrival of generics 00:27:45.640 --> 00:27:47.940 made a big difference in cost? Oh, almost certainly. 00:27:48.460 --> 00:27:50.900 When those first generics hit the market, you 00:27:50.900 --> 00:27:53.160 know, the FDA approved the first generic Actos 00:27:53.160 --> 00:27:56.839 in the U .S. in 2012 and European approvals for 00:27:56.839 --> 00:27:59.180 generics like PO Glutazone Activists and Careca 00:27:59.180 --> 00:28:01.740 were around the same time, that typically leads 00:28:01.740 --> 00:28:04.740 to significant price competition. Right. So the 00:28:04.740 --> 00:28:06.740 overall cost of treatment with PO Glutazone has 00:28:06.740 --> 00:28:09.299 likely come down substantially, which in turn 00:28:09.299 --> 00:28:11.579 makes it more affordable and accessible for more 00:28:11.579 --> 00:28:13.700 patients and health care systems. But on the 00:28:13.700 --> 00:28:16.019 flip side, those massive legal settlements we 00:28:16.019 --> 00:28:18.299 talked about must have had a pretty hefty financial 00:28:18.299 --> 00:28:21.339 impact on Takeda, the originator company. Undoubtedly. 00:28:21.779 --> 00:28:24.819 Paying out $2 .4 billion to settle lawsuits is 00:28:24.819 --> 00:28:27.210 a a major financial event for any company, even 00:28:27.210 --> 00:28:29.430 a large pharmaceutical firm. That's a direct 00:28:29.430 --> 00:28:31.809 economic consequence of the safety controversies. 00:28:32.369 --> 00:28:35.210 Beyond just cost and settlements, has pioglitazone 00:28:35.210 --> 00:28:38.170 influenced the broader diabetes drug market economically? 00:28:38.609 --> 00:28:41.089 I'd say yes in a couple of ways. The development 00:28:41.089 --> 00:28:43.690 and marketing of pioglitazone and its TZD competitors 00:28:43.690 --> 00:28:45.970 definitely spurred innovation and investment 00:28:45.970 --> 00:28:48.650 in diabetes research back in the day, focusing 00:28:48.650 --> 00:28:50.930 attention on that insulin sensitization pathway. 00:28:51.099 --> 00:28:53.519 Right, pushing the science forward. Exactly. 00:28:53.880 --> 00:28:56.579 And even now, ongoing research continues to explore 00:28:56.579 --> 00:28:59.720 potential new uses for pioglitazone, or to refine 00:28:59.720 --> 00:29:01.700 our understanding of its long -term effects, 00:29:01.900 --> 00:29:04.549 both good and bad. And those findings can continue 00:29:04.549 --> 00:29:07.150 to influence its economic value and its place 00:29:07.150 --> 00:29:09.670 in treatment guidelines relative to newer agents. 00:29:10.130 --> 00:29:11.970 Okay, finally, let's think about the cultural 00:29:11.970 --> 00:29:14.650 influence, if you can call it that. Has the story 00:29:14.650 --> 00:29:18.210 of pioglitazone shaped how we think or talk about 00:29:18.210 --> 00:29:21.509 diabetes, medications, or drug safety more broadly? 00:29:21.750 --> 00:29:23.910 I think it has, yeah. The whole pioglitazone 00:29:23.910 --> 00:29:26.250 saga, especially the controversies, serves as 00:29:26.250 --> 00:29:28.650 a really potent case study. It highlights the 00:29:28.650 --> 00:29:30.869 complexities involved in managing a chronic disease 00:29:30.869 --> 00:29:33.950 like type 2 diabetes over many years, often with 00:29:33.950 --> 00:29:36.369 multiple medications. And the safety issues definitely 00:29:36.369 --> 00:29:38.609 brought things into public focus. Absolutely. 00:29:39.410 --> 00:29:42.250 The concerns, particularly around bladder cancer, 00:29:42.809 --> 00:29:45.630 really fueled public discourse and continue to 00:29:45.630 --> 00:29:48.700 about drug safety in general. It made people 00:29:48.700 --> 00:29:51.740 ask questions about how drugs are tested, how 00:29:51.740 --> 00:29:53.900 risks are monitored after approval, that's called 00:29:53.900 --> 00:29:56.380 post -market surveillance, how regulatory agencies 00:29:56.380 --> 00:29:59.259 make decisions, and what responsibilities pharmaceutical 00:29:59.259 --> 00:30:01.880 companies have to be transparent about potential 00:30:01.880 --> 00:30:04.319 risks. You can definitely see those themes playing 00:30:04.319 --> 00:30:07.160 out online in patient forums and discussions 00:30:07.160 --> 00:30:09.440 about different drugs. You really can. People 00:30:09.440 --> 00:30:11.819 share experiences, concerns about side effects, 00:30:12.220 --> 00:30:14.079 questions about whether a drug is truly safe 00:30:14.079 --> 00:30:16.720 or effective for them. Pio Goodison's story is 00:30:16.720 --> 00:30:19.279 part of that larger conversation. Has it changed 00:30:19.279 --> 00:30:21.539 how doctors and patients talk about these drugs? 00:30:21.779 --> 00:30:23.880 I think it's contributed to a greater awareness 00:30:23.880 --> 00:30:27.000 on both sides of the need for careful monitoring 00:30:27.000 --> 00:30:30.279 and really individualized risk -benefit assessment. 00:30:30.819 --> 00:30:32.640 It's pushed for better communication about not 00:30:32.640 --> 00:30:34.980 just the potential upsides of a medication, but 00:30:34.980 --> 00:30:37.079 the potential downsides too. And maybe shifted 00:30:37.079 --> 00:30:39.859 the scientific focus a bit too. Yes, definitely. 00:30:40.259 --> 00:30:42.579 As we discussed, the development of pioglutazone 00:30:42.579 --> 00:30:44.480 as an insulin sensitizer was important because 00:30:44.480 --> 00:30:46.700 it really highlighted the critical role of insulin 00:30:46.700 --> 00:30:49.900 resistance in type 2 diabetes. It helped shift 00:30:49.900 --> 00:30:52.579 the focus. partly away from just thinking about 00:30:52.579 --> 00:30:55.440 stimulating more insulin secretion towards addressing 00:30:55.440 --> 00:30:58.240 how well the body uses the insulin it has. And 00:30:58.240 --> 00:31:00.640 of course, more recently, the landscape has shifted 00:31:00.640 --> 00:31:03.319 again with the arrival of newer classes of diabetes 00:31:03.319 --> 00:31:06.779 drugs like SGLT2 inhibitors and GLP1 receptor 00:31:06.779 --> 00:31:09.339 agonists that have shown clear cardiovascular 00:31:09.339 --> 00:31:12.859 benefits in major trials. That's definitely impacted 00:31:12.859 --> 00:31:15.859 where an older drug like piaglitazone now fits 00:31:15.859 --> 00:31:18.259 into the treatment algorithms. It reflects a 00:31:18.259 --> 00:31:20.869 dynamic, evolving understanding of how best to 00:31:20.869 --> 00:31:22.829 manage diabetes and its complications. That's 00:31:22.829 --> 00:31:25.589 a constantly changing field. Okay, so let's try 00:31:25.589 --> 00:31:27.950 to wrap this up. For you, the listener, who might 00:31:27.950 --> 00:31:30.329 be trying to process all this information, what 00:31:30.329 --> 00:31:33.109 are the key takeaways from our deep dive into 00:31:33.109 --> 00:31:35.309 pioglitazone? Well, I think the main thing is 00:31:35.309 --> 00:31:37.470 that pioglitazone represents a really unique 00:31:37.470 --> 00:31:40.130 way to tackle type 2 diabetes by focusing on 00:31:40.130 --> 00:31:42.869 that core problem of insulin resistance. It can 00:31:42.869 --> 00:31:44.910 be an effective tool for lowering blood sugar. 00:31:45.079 --> 00:31:48.440 But its journey has been complex. It's shown 00:31:48.440 --> 00:31:51.059 promise, but it's also been marked by significant 00:31:51.059 --> 00:31:53.799 safety concerns, especially the blighter cancer 00:31:53.799 --> 00:31:56.940 risk, but also the issues around edema, heart 00:31:56.940 --> 00:32:00.019 failure, and fractures. It's a reminder that 00:32:00.019 --> 00:32:02.559 few medications come without potential downsides, 00:32:02.900 --> 00:32:04.980 and our scientific understanding of exactly how 00:32:04.980 --> 00:32:07.299 it works and the full balance of its effects 00:32:07.299 --> 00:32:10.079 is something that continues to evolve even now. 00:32:10.160 --> 00:32:12.259 So hopefully this discussion has given you a 00:32:12.259 --> 00:32:15.539 much clearer understanding of pioglitazone, moving 00:32:15.539 --> 00:32:17.720 beyond just seeing the name on a pill bottle. 00:32:18.299 --> 00:32:20.099 Understanding its history, the science behind 00:32:20.099 --> 00:32:23.240 it, the regulatory ups and downs really empowers 00:32:23.240 --> 00:32:25.299 you, doesn't it? Absolutely. It equips you to 00:32:25.299 --> 00:32:28.099 have more informed, more confident conversations 00:32:28.099 --> 00:32:30.700 with your doctor or pharmacist about your own 00:32:30.700 --> 00:32:32.559 health or perhaps the health of someone you care 00:32:32.559 --> 00:32:34.619 about who might be taking this medication. And 00:32:34.619 --> 00:32:37.180 as we look ahead, maybe a final provocative thought 00:32:37.180 --> 00:32:39.519 to leave you with. Yeah, I think... Considering 00:32:39.519 --> 00:32:41.480 everything we've discussed, the ongoing research, 00:32:42.200 --> 00:32:44.339 the established role, but also the known risks, 00:32:44.480 --> 00:32:46.920 and importantly, the emergence of these newer 00:32:46.920 --> 00:32:49.460 diabetes treatments with proven cardiovascular 00:32:49.460 --> 00:32:52.579 benefits, it really raises a fascinating question 00:32:52.579 --> 00:32:54.680 for the future, doesn't it? It does. What will 00:32:54.680 --> 00:32:57.420 the role of insulin sensitizer or the paglidazone 00:32:57.420 --> 00:33:00.019 actually be in the diabetes treatment landscape? 00:33:00.380 --> 00:33:03.319 five, 10, 20 years from now, how do we continue 00:33:03.319 --> 00:33:06.200 to balance the established efficacy of older 00:33:06.200 --> 00:33:08.539 drugs like this with our evolving knowledge of 00:33:08.539 --> 00:33:10.799 their long -term safety and the growing availability 00:33:10.799 --> 00:33:13.140 of potentially safer or more beneficial alternatives 00:33:13.140 --> 00:33:15.059 is a story that's definitely still unfolding.