WEBVTT 00:00:00.000 --> 00:00:02.339 You know, it's easy to think our modern medicine 00:00:02.339 --> 00:00:04.480 is just sort of appeared fully formed. Right. 00:00:04.559 --> 00:00:08.000 But the reality is often this amazing long journey, 00:00:08.720 --> 00:00:11.480 centuries sometimes. Did you know some of today's 00:00:11.480 --> 00:00:14.160 treatments have roots way back in the Middle 00:00:14.160 --> 00:00:18.600 Ages? It's wild. It really is. OK, let's unpack 00:00:18.600 --> 00:00:20.800 this, because in this deep dive, we're focusing 00:00:20.800 --> 00:00:23.739 on metformin. I mean. It's a super common drug 00:00:23.739 --> 00:00:26.660 for type 2 diabetes. Oh, absolutely. But it's 00:00:26.660 --> 00:00:29.600 so much more than just a daily pill for many 00:00:29.600 --> 00:00:32.619 people. The story behind it connects traditional 00:00:32.619 --> 00:00:35.899 medicine, how we understand diabetes, and some 00:00:35.899 --> 00:00:38.240 really surprising twists. Exactly. And that's 00:00:38.240 --> 00:00:39.880 what we really want to explore with you today. 00:00:40.020 --> 00:00:41.600 We're not just going to cover what metformin 00:00:41.600 --> 00:00:45.020 does right now. We'll dig into its, well, surprisingly 00:00:45.020 --> 00:00:48.299 old origins, trace how science figured it out, 00:00:48.460 --> 00:00:50.380 understand how it actually works in your body, 00:00:50.479 --> 00:00:53.020 and even touch on some regulatory hurdles and 00:00:53.020 --> 00:00:55.340 its wider impact. Yeah, the goal is really to 00:00:55.340 --> 00:00:57.299 give you a clear, kind of insightful picture 00:00:57.299 --> 00:01:00.039 of this drug. So you feel properly informed, 00:01:00.240 --> 00:01:02.280 but hopefully not bogged down in technical stuff. 00:01:02.719 --> 00:01:04.719 Right. And to do that, we've looked at, well, 00:01:04.900 --> 00:01:08.200 a whole range of things. We have scientific reports 00:01:08.200 --> 00:01:11.060 on the mechanisms, clinical reviews on how well 00:01:11.060 --> 00:01:13.719 it works, historical accounts, manufacturing 00:01:13.719 --> 00:01:16.819 info. even cultural perspectives on managing 00:01:16.819 --> 00:01:19.439 diabetes. It's a multifaceted approach, hoping 00:01:19.439 --> 00:01:21.859 to give a really rich understanding. Hopefully. 00:01:22.359 --> 00:01:24.840 So where does this whole story kick off? It's 00:01:24.840 --> 00:01:27.140 pretty amazing, actually. We have to go way back. 00:01:27.540 --> 00:01:29.739 Middle ages kind of back. Yeah, to a plant called 00:01:29.739 --> 00:01:33.159 Gallega officinalis. Goats roe, right. Or French 00:01:33.159 --> 00:01:36.280 lilac. That's the one. Traditional healers back 00:01:36.280 --> 00:01:38.060 then noticed it seemed to help with symptoms 00:01:38.060 --> 00:01:41.560 we now link to diabetes, like frequent urination. 00:01:41.769 --> 00:01:44.390 And this folk knowledge persisted for hundreds 00:01:44.390 --> 00:01:47.150 of years. It did. Then, fast forward to the early 00:01:47.150 --> 00:01:49.549 20th century, scientists started asking, OK, 00:01:49.769 --> 00:01:52.510 what in this plant is doing this? And they found 00:01:52.510 --> 00:01:55.090 compounds called guanidines. Yeah, a critical 00:01:55.090 --> 00:01:57.150 finding. They saw guanidine could lower blood 00:01:57.150 --> 00:01:59.329 glucose. Big problem, though. It's too toxic. 00:01:59.530 --> 00:02:02.290 Exactly. Too toxic for widespread safe use in 00:02:02.290 --> 00:02:04.930 people. OK, so back to the drawing board. Sort 00:02:04.930 --> 00:02:07.189 of. They looked for safer things in the plant. 00:02:07.400 --> 00:02:10.939 Right. And by 1923, they'd identified a less 00:02:10.939 --> 00:02:15.000 toxic relative called galagene. Isoamaline guanidine, 00:02:15.280 --> 00:02:18.180 technically. And early human studies looked promising. 00:02:18.360 --> 00:02:20.860 They did. It lowered blood sugar in diabetics, 00:02:20.939 --> 00:02:23.340 but didn't really affect people with normal blood 00:02:23.340 --> 00:02:25.460 sugar much. OK, here's where it gets really interesting, 00:02:25.780 --> 00:02:28.979 though. Because around the same time, 1922, actually, 00:02:29.580 --> 00:02:32.460 chemists Werner and Bell synthesized metformin 00:02:32.460 --> 00:02:37.360 itself. 11 -dimethyl big one -eyed. But... And 00:02:37.360 --> 00:02:39.439 this is a key point. Even though they made it 00:02:39.439 --> 00:02:42.500 early on, it wasn't the focus. Why not? Well, 00:02:42.699 --> 00:02:44.719 the attention initially went to other related 00:02:44.719 --> 00:02:47.620 compounds, other biguanides, specifically finformin 00:02:47.620 --> 00:02:50.120 and buformin. Ah, because they seem stronger, 00:02:50.340 --> 00:02:52.419 more potent, glucose lower. They seem to have 00:02:52.419 --> 00:02:54.599 a more powerful effect, yeah. So for a while, 00:02:54.699 --> 00:02:57.520 metformin was kind of forgotten, pushed aside 00:02:57.520 --> 00:02:59.719 because these others looked more promising. Wow. 00:02:59.960 --> 00:03:01.759 Shows how research can take different paths. 00:03:02.199 --> 00:03:05.039 But something brought biguanides back. It did, 00:03:05.439 --> 00:03:07.439 and kind of accidentally. During World War II, 00:03:07.740 --> 00:03:09.960 a big one -eyed being tested for malaria. No 00:03:09.960 --> 00:03:11.659 way. Yeah, it was found to have a side effect 00:03:11.659 --> 00:03:14.580 of lowering blood glucose. Huh, so that's Birdmoor 00:03:14.580 --> 00:03:17.400 research. It inspired a French doctor, Jean Stern, 00:03:17.780 --> 00:03:20.300 to look specifically at metformin again, but 00:03:20.300 --> 00:03:23.439 this time for what they called adult -onset diabetes 00:03:23.439 --> 00:03:26.240 back then. And his work was key. Absolutely crucial. 00:03:26.360 --> 00:03:29.979 In the late 50s, 57, 58, he published studies 00:03:29.979 --> 00:03:32.699 showing metformin worked. It lowered blood glucose 00:03:32.699 --> 00:03:35.199 effectively in type 2 diabetes. And crucially, 00:03:35.919 --> 00:03:39.020 without the big risks. Right. Without causing 00:03:39.020 --> 00:03:41.479 hypoglycemia, that dangerous low blood sugar, 00:03:41.860 --> 00:03:44.120 or the lactic acidosis buildup that was becoming 00:03:44.120 --> 00:03:46.819 a concern with finformin and buformin in some 00:03:46.819 --> 00:03:49.620 studies. So that safety profile was the big difference. 00:03:49.759 --> 00:03:52.389 It seemed to be. Based on his early work. And 00:03:52.389 --> 00:03:54.409 that led to metformin being introduced in the 00:03:54.409 --> 00:03:57.129 UK and other parts of Europe, starting in 1958. 00:03:57.449 --> 00:03:59.210 But, and this might surprise people, it took 00:03:59.210 --> 00:04:02.030 ages to get approved in the U .S. It did. Not 00:04:02.030 --> 00:04:05.509 until 1994 for FDA approval, and it hit the market 00:04:05.509 --> 00:04:08.710 there in 95. Why the long delay? Mostly lingering 00:04:08.710 --> 00:04:11.949 concerns. Worries about lactic acidosis and maybe 00:04:11.949 --> 00:04:14.449 cardiovascular effects, largely based on the 00:04:14.449 --> 00:04:16.569 negative experiences with those other big one 00:04:16.569 --> 00:04:18.680 -eyed sinformin and metformin. Right. So the 00:04:18.680 --> 00:04:20.459 history of the whole drug class kind of cast 00:04:20.459 --> 00:04:23.439 a shadow. It really shows how rigorous and sometimes 00:04:23.439 --> 00:04:26.920 slow the regulatory process can be and how past 00:04:26.920 --> 00:04:29.259 experiences, good and bad, influence things. 00:04:29.519 --> 00:04:32.000 OK, so quite a backstory to become the standard 00:04:32.000 --> 00:04:34.639 it is today. Speaking of which, let's get into 00:04:34.639 --> 00:04:37.319 its clinical uses now. I mean, it's fundamental 00:04:37.319 --> 00:04:39.439 for type 2 diabetes treatment. Oh, absolutely. 00:04:39.720 --> 00:04:42.040 It's the recommended first line therapy for most 00:04:42.040 --> 00:04:45.060 people diagnosed with P2DM and for very good 00:04:45.060 --> 00:04:47.300 reasons. Its main job is lowering blood sugar, 00:04:47.319 --> 00:04:49.970 right? Both fasting and after meals. Correct. 00:04:50.110 --> 00:04:52.970 It lowers both your basal or fasting glucose 00:04:52.970 --> 00:04:55.569 and your post cranial glucose, the spike after 00:04:55.569 --> 00:04:57.959 you eat. It does this in a few ways. The liver 00:04:57.959 --> 00:04:59.740 is a big part of it. That's the main one, yes. 00:05:00.240 --> 00:05:02.620 It works primarily by inhibiting the liver's 00:05:02.620 --> 00:05:05.259 production of glucose. That process is called 00:05:05.259 --> 00:05:08.279 gluconeogenesis. So it tells the liver's backup 00:05:08.279 --> 00:05:11.079 glipose factory to slow down production. That's 00:05:11.079 --> 00:05:13.060 a good way to put it. But it also helps in other 00:05:13.060 --> 00:05:15.500 ways. It reduces how much glucose you absorb 00:05:15.500 --> 00:05:18.000 from your food in the gut. OK. And it improves 00:05:18.000 --> 00:05:20.560 how your body's cells, especially muscle cells, 00:05:21.000 --> 00:05:23.420 respond to insulin and take up glucose from the 00:05:23.420 --> 00:05:25.399 blood. And a key point you mentioned earlier, 00:05:26.560 --> 00:05:29.660 when used alone for type 2 diabetes, it generally 00:05:29.660 --> 00:05:32.259 doesn't cause hypoglycemia. That's a major advantage, 00:05:32.699 --> 00:05:35.300 yeah. Unlike some other diabetes drugs, the risk 00:05:35.300 --> 00:05:38.379 of dangerously low blood sugar is very low with 00:05:38.379 --> 00:05:40.879 metformin monotherapy. And the benefits seem 00:05:40.879 --> 00:05:43.480 to go beyond just sugar control. We hear about 00:05:43.480 --> 00:05:46.220 weight, maybe lipids. That's right. Research 00:05:46.220 --> 00:05:48.660 suggests it can contribute to modest weight reduction, 00:05:48.819 --> 00:05:50.639 or at least weight neutrality, which is helpful. 00:05:51.100 --> 00:05:53.240 It can also help improve lipid profiles, lowering 00:05:53.240 --> 00:05:56.379 LDL cholesterol and triglycerides. And there's 00:05:56.379 --> 00:05:58.379 evidence suggesting it plays a role in preventing 00:05:58.379 --> 00:06:01.019 vascular complications. Thinking about bigger 00:06:01.019 --> 00:06:05.029 studies. The UK PDS comes to mind. Yes. The UK 00:06:05.029 --> 00:06:08.529 perspective diabetes study back in 1998 was landmark. 00:06:09.110 --> 00:06:11.029 It provided strong evidence that metformin not 00:06:11.029 --> 00:06:13.509 only improved glucose control, but also reduced 00:06:13.509 --> 00:06:15.610 the risk of cardiovascular disease and death 00:06:15.610 --> 00:06:18.550 from any cause, particularly in overweight patients. 00:06:19.170 --> 00:06:21.810 This was seen in those with normal or only mildly 00:06:21.810 --> 00:06:24.310 reduced kidney function at the time. And newer 00:06:24.310 --> 00:06:26.930 studies seem to back this up. They do. For instance, 00:06:27.110 --> 00:06:31.680 the RIAC Italian study from 2013 suggested metformin 00:06:31.680 --> 00:06:33.759 was linked to a lower rate of cardiovascular 00:06:33.759 --> 00:06:36.720 disease across different age groups and different 00:06:36.720 --> 00:06:39.360 levels of kidney function compared to other diabetes 00:06:39.360 --> 00:06:41.680 treatments. OK, that brings up the kidney function 00:06:41.680 --> 00:06:43.860 point. That's been a bit of a moving target, 00:06:43.879 --> 00:06:46.540 hasn't it? It has. For a long time, there was 00:06:46.540 --> 00:06:49.360 a lot of caution, even contraindication, for 00:06:49.360 --> 00:06:51.600 using metformin if someone had kidney problems 00:06:51.600 --> 00:06:54.300 because of that lactic acidosis concern. Right. 00:06:54.519 --> 00:06:57.660 But that thinking has shifted. Yes. Significantly. 00:06:57.939 --> 00:07:00.240 Current guidelines now generally recommend that 00:07:00.240 --> 00:07:03.240 metformin can often be continued, although maybe 00:07:03.240 --> 00:07:05.959 at a reduced dose, in patients with moderate 00:07:05.959 --> 00:07:08.519 kidney impairment. We're talking a GFR, that 00:07:08.519 --> 00:07:10.779 measure of kidney filtration, between 30 and 00:07:10.779 --> 00:07:12.879 59 milliliters per minute. And the rationale 00:07:12.879 --> 00:07:15.240 for that change? Well, there are a couple things. 00:07:15.579 --> 00:07:17.939 One is recognizing that stopping metformin might 00:07:17.939 --> 00:07:20.579 mean losing its pinchual cardiovascular benefits 00:07:20.579 --> 00:07:23.310 in a group already at higher risk. Okay. And 00:07:23.310 --> 00:07:26.410 two, switching to alternatives like insulin or 00:07:26.410 --> 00:07:28.910 sulfonylureas might actually increase the risk 00:07:28.910 --> 00:07:30.930 of other problems, particularly hypoglycemia. 00:07:31.110 --> 00:07:33.029 That makes sense, weighing the different risks. 00:07:33.310 --> 00:07:36.329 Exactly. There was even one retrospective study 00:07:36.329 --> 00:07:39.790 in 2015 looking at patients with severe stage 00:07:39.790 --> 00:07:42.990 five kidney disease who were on specific anemia 00:07:42.990 --> 00:07:46.180 drugs. Even though metformin was technically 00:07:46.180 --> 00:07:48.740 contraindicated, the patients in that study who 00:07:48.740 --> 00:07:51.800 were taking it didn't show a statistically significant 00:07:51.800 --> 00:07:54.040 increase in metabolic acidosis risk compared 00:07:54.040 --> 00:07:56.720 to those who weren't. Interesting. But still 00:07:56.720 --> 00:07:59.279 caution needed. Oh, definitely. The guidelines 00:07:59.279 --> 00:08:02.220 still generally say stop metformin if the GFR 00:08:02.220 --> 00:08:05.240 drops below 30. The risk does increase with more 00:08:05.240 --> 00:08:07.899 severe kidney disease, but it highlights this 00:08:07.899 --> 00:08:10.500 evolving picture and the need for individual 00:08:10.500 --> 00:08:13.000 assessment. It's not just for established diabetes, 00:08:13.199 --> 00:08:15.040 either. What about pre -diabetes? Yes, that's 00:08:15.040 --> 00:08:17.939 another area. Several big analyses in the American 00:08:17.939 --> 00:08:20.259 Diabetes Association suggest metformin can be 00:08:20.259 --> 00:08:22.660 considered alongside lifestyle changes, of course. 00:08:22.879 --> 00:08:25.100 Lifestyle first, though. Lifestyle is definitely 00:08:25.100 --> 00:08:27.680 more effective and the primary recommendation. 00:08:28.579 --> 00:08:31.100 But metformin might be an option to help lower 00:08:31.100 --> 00:08:33.460 the risk of progressing to full type 2 diabetes, 00:08:34.220 --> 00:08:35.720 especially for certain people, maybe those under 00:08:35.720 --> 00:08:39.669 60. those with a very high BMI, or women with 00:08:39.669 --> 00:08:42.370 a history of gestational diabetes. And the research 00:08:42.370 --> 00:08:45.110 story continues, looking beyond type 2. Right. 00:08:45.230 --> 00:08:47.210 There are several emerging areas that are quite 00:08:47.210 --> 00:08:49.169 exciting, actually. Like what? Well, gestational 00:08:49.169 --> 00:08:52.590 diabetes, for one. Some studies, like ones from 00:08:52.590 --> 00:08:55.269 Canada and Australia, suggest metformin can lead 00:08:55.269 --> 00:08:57.950 to better glucose control during pregnancy, reduce 00:08:57.950 --> 00:09:00.409 the need for insulin injections, and maybe even 00:09:00.409 --> 00:09:02.750 lower the rate of C -sections compared to placebo 00:09:02.750 --> 00:09:05.529 or insulin. Are there any downsides there? There 00:09:05.529 --> 00:09:08.129 are some considerations. Some studies noted potentially 00:09:08.129 --> 00:09:10.629 lower birth weights and maybe a slightly higher 00:09:10.629 --> 00:09:13.730 chance of babies being born small for their gestational 00:09:13.730 --> 00:09:16.370 age. So it's still being actively studied and 00:09:16.370 --> 00:09:19.509 discussed. What else? Type 1 diabetes. Potentially 00:09:19.509 --> 00:09:22.049 as an add -on therapy for people with type 1 00:09:22.049 --> 00:09:25.490 who are also overweight or obese. The idea is 00:09:25.490 --> 00:09:27.590 to help manage the insulin resistance that can 00:09:27.590 --> 00:09:30.159 sometimes develop alongside type 1. And then 00:09:30.159 --> 00:09:32.019 there's the cancer connection we sometimes hear 00:09:32.019 --> 00:09:35.080 about. Yes, that's a huge area of research. Right 00:09:35.080 --> 00:09:37.379 now, large reviews haven't definitively concluded 00:09:37.379 --> 00:09:40.200 that metformin reduces overall cancer risk across 00:09:40.200 --> 00:09:43.259 the board. The results are a bit mixed, maybe 00:09:43.259 --> 00:09:46.019 inconclusive. But research is ongoing. Very much 00:09:46.019 --> 00:09:48.480 so. Scientists are looking at its effects on 00:09:48.480 --> 00:09:51.529 specific types of tumors. in specific tissues, 00:09:51.990 --> 00:09:54.549 and even in rare genetic syndromes, like live 00:09:54.549 --> 00:09:57.350 from any, that dramatically increase cancer risk. 00:09:57.529 --> 00:09:59.690 And probably the most talked about potential 00:09:59.690 --> 00:10:03.070 use? Aging? Ah yes, the anti -aging potential. 00:10:03.110 --> 00:10:04.750 There's a lot of buzz around that. What's the 00:10:04.750 --> 00:10:07.460 thinking there? Well, studies in model organisms, 00:10:07.820 --> 00:10:10.659 like the tiny, warm C. elegans, show metformin 00:10:10.659 --> 00:10:12.899 seems to influence several fundamental pathways 00:10:12.899 --> 00:10:14.820 linked to aging. Like what kind of pathways? 00:10:14.940 --> 00:10:17.019 Things like insulin signaling, a major growth 00:10:17.019 --> 00:10:20.019 pathway called MTOR, the function of mitochondria, 00:10:20.259 --> 00:10:22.940 that sells powerhouses, an energy sensor called 00:10:22.940 --> 00:10:26.620 AMPK. It also seems to reduce oxidative stress, 00:10:27.000 --> 00:10:29.019 DNA damage, inflammation. Wow, that's a lot. 00:10:29.159 --> 00:10:32.620 It is. It also impacts processes like autophagy, 00:10:32.759 --> 00:10:35.419 which is cellular cleanup, and cellular senescence, 00:10:35.659 --> 00:10:38.000 sort of like cell aging. It even affects the 00:10:38.000 --> 00:10:40.779 gut microbes in worms, though we don't have clear 00:10:40.779 --> 00:10:43.100 evidence for that specific effect in humans yet. 00:10:43.220 --> 00:10:46.740 So the idea is it might gently nudge these core 00:10:46.740 --> 00:10:49.720 aging processes in a healthier direction? That's 00:10:49.720 --> 00:10:51.860 the hope, based on these preclinical studies. 00:10:52.399 --> 00:10:54.460 Obviously, translating that to humans is a whole 00:10:54.460 --> 00:10:57.480 other ballgame, and large clinical trials like 00:10:57.480 --> 00:11:00.590 TAME targeting aging with metformin, are designed 00:11:00.590 --> 00:11:03.070 to investigate this. Fascinating. It sounds like 00:11:03.070 --> 00:11:05.690 this old drug might still have some new tricks. 00:11:06.370 --> 00:11:08.090 So let's get into the nitty -gritty of how it 00:11:08.090 --> 00:11:11.539 works. The mechanism. Okay, so as we said, the 00:11:11.539 --> 00:11:13.940 main glucose lowering effect is shutting down 00:11:13.940 --> 00:11:16.419 excess glucose production in the liver inhibiting 00:11:16.419 --> 00:11:19.059 gluconeogenesis. But there are indirect things 00:11:19.059 --> 00:11:21.399 happening too. Yes, it's becoming clear that 00:11:21.399 --> 00:11:23.860 indirect effects contribute significantly. For 00:11:23.860 --> 00:11:26.460 instance, fat breakdown in adipose tissue releases 00:11:26.460 --> 00:11:28.940 glycerol and fatty acids. Which can fuel glucose 00:11:28.940 --> 00:11:32.909 production in the liver. Exactly. And while metformin's 00:11:32.909 --> 00:11:35.389 direct effect on fat cells isn't its main job, 00:11:35.730 --> 00:11:37.809 the overall improvement in insulin sensitivity 00:11:37.809 --> 00:11:40.710 it causes can indirectly influence these processes. 00:11:41.230 --> 00:11:43.690 Its main side of action, where it really accumulates 00:11:43.690 --> 00:11:46.730 and works, is the liver. Right. Now when you 00:11:46.730 --> 00:11:48.809 take a metformin pill, how much actually gets 00:11:48.809 --> 00:11:51.529 into your system? The oral bioavailability is 00:11:51.529 --> 00:11:54.470 around 50 to 60 percent. So about half of it 00:11:54.470 --> 00:11:56.950 gets absorbed. Where does that happen? Primarily 00:11:56.950 --> 00:11:59.480 in the small intestine. From there, it enters 00:11:59.480 --> 00:12:01.240 the bloodstream and goes straight to the liver 00:12:01.240 --> 00:12:03.440 via the portal vein. And then it spreads out. 00:12:03.840 --> 00:12:06.399 Then it gets distributed to other tissues like 00:12:06.399 --> 00:12:08.840 muscle and fat, where it helps them become more 00:12:08.840 --> 00:12:11.299 sensitive to insulin and take up glucose more 00:12:11.299 --> 00:12:13.419 effectively. How does your body get rid of it? 00:12:13.440 --> 00:12:15.759 Does it get broken down? No, that's interesting. 00:12:15.759 --> 00:12:18.200 It's not metabolized. It's excreted unchanged 00:12:18.200 --> 00:12:20.500 by the kidneys. They actively secrete it into 00:12:20.500 --> 00:12:22.940 the urine through tubules. That's the main way 00:12:22.940 --> 00:12:25.639 out. Okay. And you mentioned the gut microbiota 00:12:25.639 --> 00:12:28.750 earlier. Yes. That's a relatively newer area 00:12:28.750 --> 00:12:31.850 of understanding. Research increasingly suggests 00:12:31.850 --> 00:12:34.590 metformin significantly alters the composition 00:12:34.590 --> 00:12:36.850 and function of the gut bacteria. And that might 00:12:36.850 --> 00:12:39.899 contribute to how it works. It might. It could 00:12:39.899 --> 00:12:42.039 contribute to both the glucose lowering effects 00:12:42.039 --> 00:12:45.500 and potentially some of the common gastrointestinal 00:12:45.500 --> 00:12:47.759 side effects people experience, like diarrhea 00:12:47.759 --> 00:12:50.720 or nausea. Right, those are fairly common. Now 00:12:50.720 --> 00:12:53.539 we see different versions, like geofage versus 00:12:53.539 --> 00:12:56.820 geolucophage XR. What's the deal there? Okay, 00:12:56.980 --> 00:13:00.039 so geolucophage is the standard immediate release 00:13:00.039 --> 00:13:03.120 IR version. The drug gets released pretty quickly 00:13:03.120 --> 00:13:05.519 after you swallow the pill. And XR. extended 00:13:05.519 --> 00:13:08.320 release. Exactly. Geoleucaphage XR is designed 00:13:08.320 --> 00:13:10.779 to release the medication more slowly over a 00:13:10.779 --> 00:13:12.600 longer period. What difference does that make 00:13:12.600 --> 00:13:14.980 in the body? It generally means you get a lower 00:13:14.980 --> 00:13:16.759 peak concentration of the drug in your blood 00:13:16.759 --> 00:13:19.179 that's called C -max, and it takes longer to 00:13:19.179 --> 00:13:21.539 reach that peak that's T -max compared to the 00:13:21.539 --> 00:13:23.899 immediate release. But you still absorb the same 00:13:23.899 --> 00:13:26.659 total amount. Pretty much yes. The overall absorption, 00:13:26.740 --> 00:13:29.860 we call the AUC, or area under the curve, is 00:13:29.860 --> 00:13:32.580 similar if you compare equivalent daily doses. 00:13:33.159 --> 00:13:36.700 Like, 2 ,000 milligrams of XR once daily gives 00:13:36.700 --> 00:13:39.320 similar total exposure to 1 ,000 milligrams of 00:13:39.320 --> 00:13:42.259 IR twice daily. And it doesn't build up over 00:13:42.259 --> 00:13:44.620 time with the XR. Studies suggest it doesn't 00:13:44.620 --> 00:13:47.299 accumulate in the plasma with repeated XR dosing, 00:13:47.299 --> 00:13:50.539 which is good. The idea behind XR is often to 00:13:50.539 --> 00:13:53.100 improve gastrointestinal tolerance and allow 00:13:53.100 --> 00:13:56.259 for once daily dosing. So a smoother ride, potentially 00:13:56.259 --> 00:13:58.240 fewer side effects for some people. That's the 00:13:58.240 --> 00:14:01.000 aim. We also saw GL -U -METS I mentioned. Is 00:14:01.000 --> 00:14:03.500 that another type of XR? It is, yes. It's another 00:14:03.500 --> 00:14:06.259 modified release formulation, but it uses a different 00:14:06.259 --> 00:14:08.919 delivery technology involving polymers to release 00:14:08.919 --> 00:14:11.399 the drug primarily in the upper GI tract. Different 00:14:11.399 --> 00:14:13.980 mechanism, same goal of slower release. Does 00:14:13.980 --> 00:14:16.000 the way the body handles metformin change much 00:14:16.000 --> 00:14:19.039 with age or, say, kidney problems? It can, yes. 00:14:19.279 --> 00:14:21.399 In older adults, studies generally show that 00:14:21.399 --> 00:14:23.220 metformin clearance decreases, the body gets 00:14:23.220 --> 00:14:25.480 rid of it more slowly, the half -life might be 00:14:25.480 --> 00:14:27.259 longer, and the P concentration could be higher 00:14:27.259 --> 00:14:29.519 compared to younger folks. Mostly due to kidney 00:14:29.519 --> 00:14:32.460 function declining with age. Primarily, yes. 00:14:32.820 --> 00:14:34.899 Age -related changes in renal function are the 00:14:34.899 --> 00:14:38.080 main driver. And as we discussed, in people with 00:14:38.080 --> 00:14:40.580 diagnosed renal impairment, the pharmacokinetics 00:14:40.580 --> 00:14:42.600 definitely change depending on the severity. 00:14:42.679 --> 00:14:46.889 Oh, so. As kidney function, GFR goes down, the 00:14:46.889 --> 00:14:49.210 drug tends to stick around longer peak levels, 00:14:49.509 --> 00:14:53.889 CMACs get higher, and total exposure, AUC, increases 00:14:53.889 --> 00:14:56.029 because the kidneys just can't clear it as efficiently. 00:14:56.889 --> 00:14:59.049 There are specific tables showing how these parameters 00:14:59.049 --> 00:15:01.590 change across different stages of kidney disease. 00:15:01.649 --> 00:15:04.110 And liver problems. Interestingly, there haven't 00:15:04.110 --> 00:15:06.549 been specific pharmacokinetic studies in people 00:15:06.549 --> 00:15:09.549 with hepatic insufficiency. So we don't have 00:15:09.549 --> 00:15:12.309 clear data on how liver problems affect metformin 00:15:12.309 --> 00:15:15.299 handling. OK. What about drug interactions, things 00:15:15.299 --> 00:15:17.360 people should be careful about taking alongside 00:15:17.360 --> 00:15:19.639 metformin? Absolutely, that's important. Certain 00:15:19.639 --> 00:15:22.139 drugs can increase the risk of that rare, but 00:15:22.139 --> 00:15:24.779 serious side effect, metformin -associated lactic 00:15:24.779 --> 00:15:27.360 acidosis. Which drugs are we talking about? Generally, 00:15:27.679 --> 00:15:30.000 drugs that can also impair kidney function, cause 00:15:30.000 --> 00:15:32.019 major changes in blood pressure or circulation, 00:15:32.539 --> 00:15:35.759 mess with the body's acid -base balance, or directly 00:15:35.759 --> 00:15:38.159 interfere with metformin elimination, causing 00:15:38.159 --> 00:15:40.919 it to build up. Can you give an example? Sure. 00:15:41.320 --> 00:15:43.700 Nectartine, a calcium channel blocker used for 00:15:43.700 --> 00:15:45.980 blood pressure, has been shown to slightly increase 00:15:45.980 --> 00:15:49.960 metformin Cmax and AUC. More significantly, drugs 00:15:49.960 --> 00:15:52.519 that inhibit specific transporters in the kidney 00:15:52.519 --> 00:15:54.960 tubules responsible for secreting metformin. 00:15:55.519 --> 00:15:59.139 OCT2 and MADI transporters. Exactly. Inhibitors 00:15:59.139 --> 00:16:01.799 of those, like the anti -anginal drug Ranolazine, 00:16:02.039 --> 00:16:05.019 some cancer drugs like Vandetanib, the HIV drug 00:16:05.019 --> 00:16:08.039 Dilute Gravir, and the older heartburn medication, 00:16:08.159 --> 00:16:10.899 Semetidine. These can reduce metformin clearance. 00:16:11.019 --> 00:16:13.620 And that increases risk. Potentially, yes, by 00:16:13.620 --> 00:16:15.980 causing metformin levels to rise. The interaction 00:16:15.980 --> 00:16:17.799 with smedidine was quite significant in studies. 00:16:17.980 --> 00:16:20.440 It caused about a 60 % increase in peak metformin 00:16:20.440 --> 00:16:23.360 concentration and a 40 % increase in total exposure. 00:16:23.580 --> 00:16:25.879 Wow, so definitely important for doctors and 00:16:25.879 --> 00:16:27.480 pharmacists to check for these interactions. 00:16:27.639 --> 00:16:29.840 Crucial. Always need that complete medication 00:16:29.840 --> 00:16:32.460 list. Okay, switching gears slightly. How is 00:16:32.460 --> 00:16:34.559 this stuff actually made? It's easy to just see 00:16:34.559 --> 00:16:36.980 the pill. Yeah, the manufacturing is quite large 00:16:36.980 --> 00:16:40.360 scale. One source, a document about an API active 00:16:40.360 --> 00:16:42.519 pharmaceutical ingredient manufacturing plant. 00:16:42.779 --> 00:16:46.299 So making the raw drug powder. Right. It mentioned 00:16:46.299 --> 00:16:49.440 storing metformin hydrochloride solid in bags 00:16:49.440 --> 00:16:52.639 or drums with a potential site capacity of like 00:16:52.639 --> 00:16:55.360 100 metric tons. Gives you a sense of the volume. 00:16:55.419 --> 00:16:58.039 That's a lot. And then making the actual tablets, 00:16:58.179 --> 00:17:00.220 like those combination pills. Right. For something 00:17:00.220 --> 00:17:03.610 like Acto Plus Met XR. which combines metformin 00:17:03.610 --> 00:17:06.630 with another drug, pioglitazone, it uses specialized 00:17:06.630 --> 00:17:10.309 tech. They mentioned a scoit system single -composition 00:17:10.309 --> 00:17:12.470 osmotic tablet. What does that mean? It means 00:17:12.470 --> 00:17:14.589 they create an extended release core containing 00:17:14.589 --> 00:17:17.329 the metformin, and then they coat that core with 00:17:17.329 --> 00:17:19.309 an immediate release layer of the other drug, 00:17:19.430 --> 00:17:21.950 the pioglitazone. Clever, like a layered approach 00:17:21.950 --> 00:17:24.289 in one pill. Exactly, and we also saw a study 00:17:24.289 --> 00:17:27.029 looking at the process validation for standard 00:17:27.029 --> 00:17:28.970 metformin -sustained release tablets. What did 00:17:28.970 --> 00:17:31.710 that involve? Making sure the process works consistently. 00:17:32.039 --> 00:17:35.859 Pretty much. It detailed the steps, dry mixing 00:17:35.859 --> 00:17:38.380 the ingredients, adding lubricants so the powder 00:17:38.380 --> 00:17:40.799 flows, compressing it into tablets and packaging. 00:17:41.359 --> 00:17:43.859 But crucially, it detailed all the quality control 00:17:43.859 --> 00:17:46.740 checks. Like what? Checking the assay is the 00:17:46.740 --> 00:17:48.900 right amount of drug there. Content uniformity 00:17:48.900 --> 00:17:51.640 does each tablet have the same dose. Physical 00:17:51.640 --> 00:17:54.900 checks, size, shape, hardness they need to be 00:17:54.900 --> 00:17:57.079 strong enough, friability they shouldn't crumble 00:17:57.079 --> 00:18:00.490 easily, and dissolution testing. how quickly 00:18:00.490 --> 00:18:02.690 the drug releases. Right. Does it release over 00:18:02.690 --> 00:18:04.690 time as expected in the lab test that mimics 00:18:04.690 --> 00:18:07.480 the body? They had specific acceptance criteria, 00:18:08.099 --> 00:18:10.099 like hardness needed to be at least 5 kg in the 00:18:10.099 --> 00:18:13.740 loss, friability no more than 1 % loss, and dissolution 00:18:13.740 --> 00:18:16.039 releasing at least 80 % by a certain time point. 00:18:16.400 --> 00:18:18.619 So lots of checks along the way. Rigorous quality 00:18:18.619 --> 00:18:20.740 control is essential. Absolutely baked into the 00:18:20.740 --> 00:18:22.660 process. Now, let's talk regulation and maybe 00:18:22.660 --> 00:18:24.579 controversy. Metformin's been around, but the 00:18:24.579 --> 00:18:26.819 regulatory view has evolved, right? Especially 00:18:26.819 --> 00:18:30.460 around lactic acidosis. It really has. The European 00:18:30.460 --> 00:18:32.960 Medicines Agency, the EMA, put out a report in 00:18:32.960 --> 00:18:36.259 2016 specifically looking at this. They revised 00:18:36.259 --> 00:18:38.819 the guidance for using metformin in kidney impairment, 00:18:39.039 --> 00:18:41.299 as we discussed. And they noted the risk seemed 00:18:41.299 --> 00:18:43.880 lower than previously thought. Yes, they highlighted 00:18:43.880 --> 00:18:46.740 that the risk of fatal lactic acidosis seemed 00:18:46.740 --> 00:18:48.980 to have declined over time, from maybe around 00:18:48.980 --> 00:18:52.420 50 % in older data down to less than 20 % more 00:18:52.420 --> 00:18:54.839 recently. And the cause wasn't always just the 00:18:54.839 --> 00:18:57.000 metformin itself. That's what recent studies 00:18:57.000 --> 00:19:00.279 increasingly suggest. Lactic acidosis, when it 00:19:00.279 --> 00:19:02.559 happens in people taking metformin, is often 00:19:02.559 --> 00:19:05.000 strongly linked to underlying acute conditions. 00:19:05.099 --> 00:19:08.000 Things like shock, severe heart failure, sepsis, 00:19:08.259 --> 00:19:10.740 acute kidney injury. One study found a very high 00:19:10.740 --> 00:19:13.859 association, like a 9 .5 times higher odds, with 00:19:13.859 --> 00:19:16.079 acute kidney injury. So metformin might be present, 00:19:16.220 --> 00:19:18.500 but another serious illness is often the main 00:19:18.500 --> 00:19:20.559 driver. That seems to be the current understanding, 00:19:20.619 --> 00:19:22.480 which has led agencies like the one in Malta, 00:19:22.539 --> 00:19:24.619 for example, to officially update guidelines 00:19:24.619 --> 00:19:27.000 allowing use in moderate kidney disease, GFR. 00:19:27.210 --> 00:19:30.430 3059, with dose adjustments and monitoring, while 00:19:30.430 --> 00:19:32.529 still keeping it contraindicated below a GFR 00:19:32.529 --> 00:19:35.210 of 30. But more recently, there's been another 00:19:35.210 --> 00:19:39.390 regulatory headache. Impurities. Ah, yes, the 00:19:39.390 --> 00:19:41.369 nitrosamine issue. That definitely made headlines. 00:19:41.470 --> 00:19:43.769 And DMA, right. And nitricidamethylamine, yes. 00:19:44.609 --> 00:19:47.390 Finding this potential carcinogen as an insurity 00:19:47.390 --> 00:19:50.329 in some batches of metformin products led to 00:19:50.329 --> 00:19:52.549 significant concerns and recalls. In the U .S. 00:19:52.549 --> 00:19:55.130 and elsewhere. Yes. Regulatory agencies like 00:19:55.130 --> 00:19:58.109 the FDA and also independent labs like Valizier 00:19:58.109 --> 00:20:01.250 flag this, leading to voluntary recalls by manufacturers 00:20:01.250 --> 00:20:03.789 for affected lots. And this links back to things 00:20:03.789 --> 00:20:06.289 like that AARP article mentioning recalls due 00:20:06.289 --> 00:20:08.950 to cancer risk. Exactly. It became a major safety 00:20:08.950 --> 00:20:11.569 focus, prompting tighter controls and testing 00:20:11.569 --> 00:20:13.589 for these types of impurities in manufacturing. 00:20:13.990 --> 00:20:16.450 It's a reminder that even for very old established 00:20:16.450 --> 00:20:19.470 drugs, ongoing vigilance is critical. It really 00:20:19.470 --> 00:20:21.569 is. A wake up call about continuous monitoring. 00:20:22.159 --> 00:20:24.279 Okay, finally, let's think about the big picture 00:20:24.279 --> 00:20:27.539 economic impact cultural aspects. It's huge globally, 00:20:27.720 --> 00:20:30.990 right? Economically, its impact is massive. Being 00:20:30.990 --> 00:20:33.529 an inexpensive, widely available first -line 00:20:33.529 --> 00:20:36.829 treatment for over 60 years makes it a cornerstone 00:20:36.829 --> 00:20:39.390 of diabetes management globally, saving health 00:20:39.390 --> 00:20:41.990 care systems vast amounts compared to newer, 00:20:42.089 --> 00:20:44.349 often more expensive options. The market must 00:20:44.349 --> 00:20:47.390 be enormous. It is. The fact that specialized 00:20:47.390 --> 00:20:50.190 market research reports exist just for metformin 00:20:50.190 --> 00:20:52.710 tells you how significant it is economically. 00:20:53.009 --> 00:20:55.529 And culturally. Managing diabetes isn't just 00:20:55.529 --> 00:20:58.509 clinical, is it? Not at all. Cultural beliefs 00:20:58.509 --> 00:21:01.650 and practices play a huge role. Providing culturally 00:21:01.650 --> 00:21:04.609 competent care is so important. There are even 00:21:04.609 --> 00:21:06.609 communication models designed to help doctors 00:21:06.609 --> 00:21:08.670 understand a patient's background and beliefs 00:21:08.670 --> 00:21:11.910 about their illness. Things like ESFT, ethnic 00:21:11.910 --> 00:21:14.089 learn models. Can you give an example? Sure. 00:21:14.470 --> 00:21:16.490 Some American Indian tribes, for instance, might 00:21:16.490 --> 00:21:18.789 have specific cultural beliefs about why diabetes 00:21:18.789 --> 00:21:21.289 occurs, maybe related to external influences 00:21:21.289 --> 00:21:24.069 or changes in traditional ways. And understanding 00:21:24.069 --> 00:21:25.890 that can affect how treatment recommendations 00:21:25.890 --> 00:21:28.769 are received. Some tribal programs actively promote 00:21:28.769 --> 00:21:30.809 traditional diets as part of diabetes management. 00:21:30.990 --> 00:21:32.710 That makes sense. Or managing insulin during 00:21:32.710 --> 00:21:35.630 fasting periods. Exactly. Like during Ramadan. 00:21:36.170 --> 00:21:38.049 People need to adjust their insulin regimens 00:21:38.049 --> 00:21:40.910 carefully to avoid hypoglycemia while fasting. 00:21:41.829 --> 00:21:43.930 This often leads to preferring specific types 00:21:43.930 --> 00:21:47.049 of insulin, like basal and rapid -acting analogs, 00:21:47.329 --> 00:21:49.269 that fit better with those cultural and religious 00:21:49.269 --> 00:21:51.990 practices. It's a clear intersection of culture, 00:21:52.190 --> 00:21:55.150 belief, and medical necessity. And even the formulation 00:21:55.150 --> 00:21:57.230 matters. You mentioned a liquid version. Yes, 00:21:57.349 --> 00:21:59.910 RailMet ER, the Extended Release Oral Suspension. 00:22:00.690 --> 00:22:02.650 For people who have difficulty swallowing pills, 00:22:02.769 --> 00:22:05.289 which could be common in older adults or people 00:22:05.289 --> 00:22:07.950 with certain conditions, having a liquid option 00:22:07.950 --> 00:22:10.450 can make a huge difference in their ability and 00:22:10.450 --> 00:22:12.349 willingness to take the medication consistently. 00:22:13.170 --> 00:22:15.289 It addresses a practical barrier that can have 00:22:15.289 --> 00:22:17.940 cultural dimensions too. It's truly incredible. 00:22:18.119 --> 00:22:20.819 A single molecule, discovered almost by accident 00:22:20.819 --> 00:22:23.640 from a traditional remedy, becomes this global 00:22:23.640 --> 00:22:26.259 mainstay with such a complex story. It really 00:22:26.259 --> 00:22:29.099 is. From folk medicine, through decades of science, 00:22:29.559 --> 00:22:31.779 regulatory shifts, manufacturing challenges, 00:22:32.259 --> 00:22:34.319 and now exploring potential new roles in aging 00:22:34.319 --> 00:22:36.700 and cancer, the former's journey is far from 00:22:36.700 --> 00:22:38.960 over. So as we wrap up this deep dive, what's 00:22:38.960 --> 00:22:40.859 a final thought for our listeners to chew on? 00:22:41.140 --> 00:22:45.130 Well, maybe consider this. Given mitformin's 00:22:45.130 --> 00:22:48.009 incredibly long history and widespread use, how 00:22:48.009 --> 00:22:50.589 might research keep surprising us? Will we find 00:22:50.589 --> 00:22:53.230 completely new uses for it or will we continue 00:22:53.230 --> 00:22:55.569 to refine how we use it based on things like 00:22:55.569 --> 00:22:58.410 genetic profiles or gut microbiome analysis? 00:22:58.730 --> 00:23:01.849 Or maybe thinking about the nitrosamine issue. 00:23:02.759 --> 00:23:05.240 What does that experience tell us about the ongoing 00:23:05.240 --> 00:23:07.859 challenge of ensuring drug safety and quality, 00:23:08.299 --> 00:23:10.519 even for medications we think we know inside 00:23:10.519 --> 00:23:13.039 out after decades of use? It certainly highlights 00:23:13.039 --> 00:23:15.240 the dynamic nature of medicine and regulation, 00:23:15.859 --> 00:23:17.640 and hopefully it underscores the value of being 00:23:17.640 --> 00:23:19.220 informed and having those good conversations 00:23:19.220 --> 00:23:21.019 with your health care team about what's right 00:23:21.019 --> 00:23:23.660 for you. Maybe this dive sparked some curiosity 00:23:23.660 --> 00:23:25.539 to look deeper into the research or even the 00:23:25.539 --> 00:23:27.200 cultural side of health in your own community.