WEBVTT 00:00:00.000 --> 00:00:02.720 Welcome to the Deep Dive. Today we're taking 00:00:02.720 --> 00:00:06.280 a close look at liraglutide. It's a really interesting 00:00:06.280 --> 00:00:09.099 drug involved in managing both weight and blood 00:00:09.099 --> 00:00:11.339 sugar. Yeah, and you know, with all the buzz 00:00:11.339 --> 00:00:14.679 around newer weight loss meds lately, it feels 00:00:14.679 --> 00:00:17.920 like a good time to explore one of the, well, 00:00:18.399 --> 00:00:20.719 foundational players in this space, understand 00:00:20.719 --> 00:00:23.940 its story. Exactly. So for this deep dive, we've 00:00:23.940 --> 00:00:26.780 pulled together quite a bit of material. clinical 00:00:26.780 --> 00:00:29.399 reviews, scientific papers on its discovery, 00:00:29.660 --> 00:00:32.619 pharmacology. How it's made, the regulatory side 00:00:32.619 --> 00:00:35.240 of things, even analyses looking at its economic 00:00:35.240 --> 00:00:37.520 and social effects. It's pretty comprehensive. 00:00:38.020 --> 00:00:39.939 Definitely. So our mission today is basically 00:00:39.939 --> 00:00:42.719 to unpack liraglutide. What is it? How does it 00:00:42.719 --> 00:00:44.939 actually work? How did we get from discovering 00:00:44.939 --> 00:00:47.259 the basic science to using it in clinics? And 00:00:47.259 --> 00:00:49.100 what's the bigger picture? It's wider impact. 00:00:49.179 --> 00:00:51.369 Right. OK, let's get into it. Where do we start? 00:00:51.530 --> 00:00:53.570 The history, I suppose. Yeah, I think to really 00:00:53.570 --> 00:00:55.950 grasp lyrical glutide, you have to go back, way 00:00:55.950 --> 00:00:57.969 back actually, to the discovery of incretins. 00:00:58.049 --> 00:01:01.130 Think 1902. 1902. Yeah, Bayless and Starling. 00:01:01.450 --> 00:01:04.250 They found this chemical substance from the intestine 00:01:04.250 --> 00:01:06.730 that could stimulate the pancreas. They didn't 00:01:06.730 --> 00:01:08.109 call it incretin yet, but that was the seat. 00:01:08.250 --> 00:01:10.530 OK, so that's the very beginning. And then things 00:01:10.530 --> 00:01:13.129 picked up later with specific hormones. Right. 00:01:13.650 --> 00:01:18.010 Fast forward to the late 60s. And GIP gastric 00:01:18.010 --> 00:01:21.049 inhibitory polypeptide gets identified. That's 00:01:21.049 --> 00:01:23.409 one of the two big incretins we know. But not 00:01:23.409 --> 00:01:25.870 the only one. No, exactly. By the early 80s, 00:01:26.170 --> 00:01:27.329 researchers were pretty sure there was something 00:01:27.329 --> 00:01:30.629 else. Intestinal extracts still boosted insulin 00:01:30.629 --> 00:01:33.629 even when GIP was removed. Ah, so the hunt was 00:01:33.629 --> 00:01:35.629 on for the other player. Pretty much. And then 00:01:35.629 --> 00:01:38.829 in 83, Graham Bell in Chicago cloned the hamster 00:01:38.829 --> 00:01:41.670 pre -proglucogon gene. And inside that sequence? 00:01:42.049 --> 00:01:45.599 Was GLP -1. Bingo. Well, the blueprint for GLP 00:01:45.599 --> 00:01:48.180 -1 and GLP -2, actually. Got it. So the genetic 00:01:48.180 --> 00:01:51.239 code pointed the way, but which specific piece 00:01:51.239 --> 00:01:53.780 was the active hormone? Well, initially they 00:01:53.780 --> 00:01:56.359 thought it was a longer version, GLP -1 -137, 00:01:56.620 --> 00:02:00.620 but then two groups, Joel Heydner in Boston and 00:02:00.620 --> 00:02:03.200 Jens Juhl -Holst in Copenhagen, figured out it 00:02:03.200 --> 00:02:05.200 gets processed. Processed into shorter forms. 00:02:05.579 --> 00:02:10.580 Yeah, into GLP -1 -7 -37 and GLP -1 -7 -36 amide. 00:02:10.750 --> 00:02:12.810 Those are the active ones, the ones that really 00:02:12.810 --> 00:02:15.129 trigger insulin release. It's amazing how those 00:02:15.129 --> 00:02:17.330 little tweaks make all the difference biologically. 00:02:17.870 --> 00:02:19.370 Now, you mentioned something earlier about some 00:02:19.370 --> 00:02:22.210 mouse studies that were maybe a bit confusing. 00:02:22.949 --> 00:02:25.509 Ah, yes, that's a good point. The GLP -1 receptor 00:02:25.509 --> 00:02:28.550 knockout mice. So mice engineered without the 00:02:28.550 --> 00:02:30.830 receptor. You'd expect big problems with glucose 00:02:30.830 --> 00:02:33.770 and weight, right? You would think. Yeah. But 00:02:33.770 --> 00:02:36.349 surprisingly, their phenotype, their observable 00:02:36.349 --> 00:02:39.530 traits, were relatively mild regarding glucose 00:02:39.530 --> 00:02:43.150 metabolism and body weight. Huh. That's unexpected. 00:02:43.430 --> 00:02:45.370 It really is. It just shows that sometimes you 00:02:45.370 --> 00:02:47.550 don't see the full picture until you study it 00:02:47.550 --> 00:02:50.129 in humans, you know. So those early human studies 00:02:50.129 --> 00:02:52.090 were really crucial then. What did they show? 00:02:52.169 --> 00:02:55.069 Absolutely critical. In 1987, Crayman and his 00:02:55.069 --> 00:02:58.370 team showed definitively, yes, GLP -1 is an incretin 00:02:58.370 --> 00:03:01.310 in humans. OK, proof in people. And then in 92, 00:03:01.689 --> 00:03:03.800 gutniac at all. showed its potential against 00:03:03.800 --> 00:03:06.759 diabetes. Not just type 2, but surprisingly it 00:03:06.759 --> 00:03:08.580 showed some effect in type 1 as well. That was 00:03:08.580 --> 00:03:11.379 big. That really set the stage and these studies 00:03:11.379 --> 00:03:13.879 started revealing the key advantages we see today. 00:03:14.319 --> 00:03:17.039 Exactly. Two major things stood out early on. 00:03:17.419 --> 00:03:20.719 First, the insulin secretion was glucose dependent. 00:03:20.960 --> 00:03:23.340 Meaning it only kicks in when blood sugar is 00:03:23.340 --> 00:03:26.539 high. Precisely. Which means a much lower risk 00:03:26.539 --> 00:03:29.000 of hypoglycemia, you know, dangerously low blood 00:03:29.000 --> 00:03:31.699 sugar. That was a huge advantage over older drugs. 00:03:31.879 --> 00:03:34.460 Makes sense. And the second thing... The glucagonostatic 00:03:34.460 --> 00:03:37.840 effect. It suppresses glucagon. Glucagon tells 00:03:37.840 --> 00:03:40.159 the liver to make sugar, right? Right. So by 00:03:40.159 --> 00:03:42.939 suppressing glucagon, it helps lower the liver's... 00:03:42.990 --> 00:03:45.569 Glutose production, so you get this dual benefit, 00:03:45.969 --> 00:03:48.550 more insulin when needed, less glucose production 00:03:48.550 --> 00:03:51.069 from the liver. Very promising for type 2 diabetes. 00:03:51.289 --> 00:03:53.530 Okay, so we have the hormone, GLP -1, and we 00:03:53.530 --> 00:03:55.949 know it works well in humans. But the big problem 00:03:55.949 --> 00:03:59.849 was, it disappears really fast in the body. Native 00:03:59.849 --> 00:04:02.310 GLP -1 has a half -life of just a couple of minutes. 00:04:02.550 --> 00:04:04.689 Totally impractical as a drug you'd inject. So 00:04:04.689 --> 00:04:07.710 how did they solve that? This is where liraglutide 00:04:07.710 --> 00:04:10.129 itself starts to emerge, right? This is where 00:04:10.129 --> 00:04:14.020 the clever chemistry comes in. Around 2000, Knudsen 00:04:14.020 --> 00:04:16.600 and his team published work on designing GLP 00:04:16.600 --> 00:04:18.779 -1 derivatives that could last long enough for 00:04:18.779 --> 00:04:22.019 once daily dosing. And their trick was? Fatty 00:04:22.019 --> 00:04:25.360 acid derivatization. Basically, attaching a fatty 00:04:25.360 --> 00:04:28.439 acid chain to the GLP -1 molecule. Okay, why 00:04:28.439 --> 00:04:30.740 do that? That fatty acid acts like a handle, 00:04:31.079 --> 00:04:34.120 allowing the modified GLP -1 to bind to albumin. 00:04:34.279 --> 00:04:37.180 Albumin, the main protein in blood plasma. Exactly. 00:04:37.680 --> 00:04:40.319 By hitching a ride on albumin, The drug is shielded 00:04:40.319 --> 00:04:42.339 from the enzymes that normally chew up GLP -1 00:04:42.339 --> 00:04:44.720 very quickly, and it gets filtered out by the 00:04:44.720 --> 00:04:47.420 kidneys much slower. So it's like giving it a 00:04:47.420 --> 00:04:49.339 protective disguise and making it too big to 00:04:49.339 --> 00:04:51.100 get kicked out easily. That's a great way to 00:04:51.100 --> 00:04:53.279 put it. And that study specifically mentioned 00:04:53.279 --> 00:04:56.139 the peptide that became liraglutide as a really 00:04:56.139 --> 00:04:58.519 promising candidate. And they kept refining this 00:04:58.519 --> 00:05:02.139 idea. Oh yeah. A 2007 paper by Madsen's group 00:05:02.139 --> 00:05:04.720 dug deeper into the structure -activity relationship. 00:05:04.920 --> 00:05:07.300 They looked at how the length of the fatty acid 00:05:07.300 --> 00:05:09.240 chain and the space were connecting it to the 00:05:09.240 --> 00:05:11.560 peptide. How those details affected how well 00:05:11.560 --> 00:05:14.079 it worked and how long it lasted. Exactly. It 00:05:14.079 --> 00:05:17.360 was all about finding the sweet spot, good binding 00:05:17.360 --> 00:05:20.680 to the GLP -1 receptor, but also strong enough 00:05:20.680 --> 00:05:23.439 reversible binding to albumin for that long duration. 00:05:23.560 --> 00:05:26.019 A real molecular balancing act. It really was. 00:05:26.240 --> 00:05:29.740 And a 2005 paper also involving Biara Knudsen, 00:05:30.339 --> 00:05:32.860 really nailed down that reversible albumin binding 00:05:32.860 --> 00:05:35.399 as the key mechanism for extending the action. 00:05:35.759 --> 00:05:38.040 That paved the way for Lyraglutide. Such a cool 00:05:38.040 --> 00:05:40.920 journey from basic physiology to drug design. 00:05:41.540 --> 00:05:43.879 Okay, so we have Lyraglutide. Let's shift to 00:05:43.879 --> 00:05:46.699 how it's actually used now. What are the main 00:05:46.699 --> 00:05:49.769 approved uses? Right, so Lyraglutide... Being 00:05:49.769 --> 00:05:52.850 a GLP -1 receptor agonist has two main jobs, 00:05:53.110 --> 00:05:56.089 therapeutically speaking. First, improving glycemic 00:05:56.089 --> 00:05:58.350 -controlled blood sugar in adults and also kids, 00:05:58.449 --> 00:06:00.470 usually 10 or 12 and up, depending on the brand, 00:06:00.790 --> 00:06:03.089 with type 2 diabetes. And that's always alongside 00:06:03.089 --> 00:06:05.670 lifestyle change. Always. Diet and exercise are 00:06:05.670 --> 00:06:07.610 fundamental. It's an adjunct therapy. OK, so 00:06:07.610 --> 00:06:09.350 that's rule number one. Diabetes management, 00:06:09.389 --> 00:06:11.269 what's the second? Chronic weight management. 00:06:11.949 --> 00:06:13.709 It's approved for adults who are overweight, 00:06:13.889 --> 00:06:16.990 so a BMI of 27 or more, with a weight -related 00:06:16.990 --> 00:06:19.290 health issue, like high blood pressure or cholesterol. 00:06:19.449 --> 00:06:22.269 or adults with obesity, which is generally a 00:06:22.269 --> 00:06:25.490 BMI of 30 or more. And for kids too. Yes. Also 00:06:25.490 --> 00:06:29.129 for adolescents 12 to 17 who have obesity and 00:06:29.129 --> 00:06:31.680 weigh over 60 kilograms. And again, it's meant 00:06:31.680 --> 00:06:34.560 to be used with a reduced calorie diet and more 00:06:34.560 --> 00:06:36.600 physical activity. It's interesting that BMI 00:06:36.600 --> 00:06:39.500 criteria differ slightly depending on comorbidities. 00:06:39.800 --> 00:06:42.000 Suggests the risk -benefit calculation changes. 00:06:42.120 --> 00:06:44.240 It does. And, you know, it's not the only drug 00:06:44.240 --> 00:06:46.199 option for weight management. In Canada, for 00:06:46.199 --> 00:06:49.300 instance, you also have Orlistat and the Naltrexonobupropion 00:06:49.300 --> 00:06:52.110 combo. Lyraglutide is one. tool in the toolbox. 00:06:52.629 --> 00:06:55.069 Our clinical expert really stressed the need 00:06:55.069 --> 00:06:57.470 for a multi -component approach for obesity. 00:06:57.970 --> 00:07:00.670 Why is just diet and exercise often not enough 00:07:00.670 --> 00:07:03.689 long -term? Well, lifestyle changes, diet, activity, 00:07:04.009 --> 00:07:05.990 behavioral strategies, they absolutely should 00:07:05.990 --> 00:07:08.769 be the first line. They can work. But the reality 00:07:08.769 --> 00:07:11.269 is sustaining significant weight loss long -term 00:07:11.269 --> 00:07:13.730 with just lifestyle changes is incredibly difficult 00:07:13.730 --> 00:07:15.810 for many people. The body fights back, right? 00:07:16.110 --> 00:07:18.689 Compensatory mechanisms kick in. Precisely. Metabolism 00:07:18.689 --> 00:07:21.350 might slow down. Hunger hormones can increase. 00:07:21.730 --> 00:07:23.529 So weight regain is very common, unfortunately. 00:07:23.889 --> 00:07:26.170 And that's where medications like liraglutide 00:07:26.170 --> 00:07:28.529 can potentially help. Yes, they can be a really 00:07:28.529 --> 00:07:30.810 valuable addition. They can help people achieve 00:07:30.810 --> 00:07:33.189 more weight loss initially and maybe more importantly 00:07:33.189 --> 00:07:36.709 help maintain it. Our expert noted that even 00:07:36.709 --> 00:07:40.110 losing 5 to 10 kilos, which might sound modest, 00:07:40.470 --> 00:07:42.170 can bring clinically meaningful improvements 00:07:42.170 --> 00:07:44.089 in things like cholesterol and blood pressure. 00:07:44.689 --> 00:07:47.310 So if someone starts sex endo, the weight management 00:07:47.310 --> 00:07:50.550 version, what's the dosing like? Is it straightforward? 00:07:50.850 --> 00:07:53.509 It's a gradual process. You start low, typically 00:07:53.509 --> 00:07:56.389 0 .6 milligrams injected once a day. OK. Then 00:07:56.389 --> 00:07:58.970 you increase the dose each week, usually by 0 00:07:58.970 --> 00:08:02.110 .6 milligrams over about four weeks, until you 00:08:02.110 --> 00:08:04.310 reach the target maintenance dose of 3 milligrams 00:08:04.310 --> 00:08:07.660 daily. Why the slow ramp up? Mainly to help manage 00:08:07.660 --> 00:08:10.079 side effects, particularly nausea, which can 00:08:10.079 --> 00:08:12.240 be common at the beginning. It gives the body 00:08:12.240 --> 00:08:15.180 time to adjust. Makes sense. And is there a checkpoint, 00:08:15.439 --> 00:08:17.399 a time to see if it's actually working for that 00:08:17.399 --> 00:08:20.060 person? Yes, there is. Generally, after someone's 00:08:20.060 --> 00:08:22.420 been on the full three milligram dose for 16 00:08:22.420 --> 00:08:24.920 weeks, so about four months, you assess their 00:08:24.920 --> 00:08:27.110 weight loss. And what's the benchmark? If they 00:08:27.110 --> 00:08:29.290 haven't lost at least 4 % of their initial body 00:08:29.290 --> 00:08:31.350 weight by that point, the guidelines suggest 00:08:31.350 --> 00:08:33.850 it's less likely they'll get a significant long 00:08:33.850 --> 00:08:35.929 -term benefit, and stopping the medication should 00:08:35.929 --> 00:08:39.409 be considered. That's a useful, practical guideline 00:08:39.409 --> 00:08:41.929 for decision -making. What about using it in 00:08:41.929 --> 00:08:44.190 type 2 diabetes? Is it often combined with other 00:08:44.190 --> 00:08:46.950 meds? Oh, absolutely. The Big Phase 3 trials 00:08:46.950 --> 00:08:49.110 showed it works well in combination with many 00:08:49.110 --> 00:08:53.129 standard diabetes drugs. Metformin, sulfonylureas, 00:08:53.490 --> 00:08:56.980 TZDs, even basal insulin. So it's quite versatile 00:08:56.980 --> 00:08:59.259 in fitting into different treatment regimens. 00:08:59.399 --> 00:09:01.580 Very much so. It shows it can be useful at various 00:09:01.580 --> 00:09:03.879 stages of type 2 diabetes management. And beyond 00:09:03.879 --> 00:09:05.879 just lowering blood sugar in those patients, 00:09:06.360 --> 00:09:09.000 did the trials show other benefits? Yes, and 00:09:09.000 --> 00:09:10.879 this is quite important. In people with type 00:09:10.879 --> 00:09:13.620 2 diabetes, laryl glutide was also shown to help 00:09:13.620 --> 00:09:16.379 with weight reduction, lower systolic blood pressure, 00:09:16.500 --> 00:09:18.519 and there's even evidence suggesting it might 00:09:18.519 --> 00:09:20.659 improve the function of the pancreatic. beta 00:09:20.659 --> 00:09:24.200 cells, the insulin producers. Those are significant 00:09:24.200 --> 00:09:27.259 extra benefits, like pleiotropic effects. Exactly. 00:09:27.480 --> 00:09:29.879 It adds to its value in managing such a complex 00:09:29.879 --> 00:09:33.059 disease. I also recall something about pre -diabetes, 00:09:33.639 --> 00:09:36.960 preventing the progression. Yes. An extension 00:09:36.960 --> 00:09:39.419 phase of one of the big studies, study 1839, 00:09:39.860 --> 00:09:42.539 found that the three milligram dose of liraglutide 00:09:42.539 --> 00:09:45.879 was significantly better than placebo at delaying 00:09:45.879 --> 00:09:49.179 or even preventing the progression from pre -diabetes 00:09:49.179 --> 00:09:52.500 to full -blown type 2 diabetes. That's potentially 00:09:52.500 --> 00:09:55.419 huge for early intervention. It really is. Yeah. 00:09:55.600 --> 00:09:57.559 Suggests a role for people at high risk. Our 00:09:57.559 --> 00:10:00.080 expert also mentioned using it around bariatric 00:10:00.080 --> 00:10:02.320 surgery. Yeah, that was interesting. Apparently, 00:10:02.419 --> 00:10:04.500 it's sometimes used before surgery, but more 00:10:04.500 --> 00:10:06.840 often after. especially if someone starts regaining 00:10:06.840 --> 00:10:09.879 weight, which can happen. The 3 -milligram dose 00:10:09.879 --> 00:10:12.220 is used to help manage that post -surgical regain. 00:10:12.399 --> 00:10:14.720 underscores that weight management is often a 00:10:14.720 --> 00:10:17.659 long -term challenge, even after surgery. The 00:10:17.659 --> 00:10:19.720 expert also made a point about when to consider 00:10:19.720 --> 00:10:23.039 medication, not necessarily just as a last resort. 00:10:23.299 --> 00:10:25.720 That's right. While lifestyle is the foundation, 00:10:26.200 --> 00:10:28.639 pharmacotherapy like liraglutide can be considered 00:10:28.639 --> 00:10:31.580 earlier, especially for people with higher BMIs 00:10:31.580 --> 00:10:34.220 or those who've tried lifestyle changes but haven't 00:10:34.220 --> 00:10:36.240 been able to sustain the loss. Because of those 00:10:36.240 --> 00:10:38.750 compensatory mechanisms we talked about. Exactly. 00:10:39.289 --> 00:10:41.470 The long -term data for just lifestyle interventions 00:10:41.470 --> 00:10:44.169 can be a bit discouraging because the body adapts. 00:10:44.470 --> 00:10:47.710 But, and this is crucial, liraglutide for weight 00:10:47.710 --> 00:10:50.070 management should always be combined with ongoing 00:10:50.070 --> 00:10:53.110 lifestyle efforts. They work together. Makes 00:10:53.110 --> 00:10:55.990 sense. What about combining liraglutide with 00:10:55.990 --> 00:10:59.029 other weight loss drugs, like or Eulastat or 00:10:59.029 --> 00:11:01.929 Naltrex and Dupropion? Is that done? Well, combination 00:11:01.929 --> 00:11:04.190 therapy is standard practice in things like type 00:11:04.190 --> 00:11:06.649 2 diabetes or high blood pressure. But for weight 00:11:06.649 --> 00:11:09.490 loss, specifically combining liraglutide with 00:11:09.490 --> 00:11:11.870 those other drugs, there isn't a lot of strong 00:11:11.870 --> 00:11:14.029 evidence supporting it right now. So not a routine 00:11:14.029 --> 00:11:16.309 thing, maybe more of an individual clinical decision? 00:11:16.429 --> 00:11:18.879 Pretty much. Some doctors might try it based 00:11:18.879 --> 00:11:20.639 on the different ways the drugs work, but we 00:11:20.639 --> 00:11:22.679 need more research to really know if it's effective 00:11:22.679 --> 00:11:25.399 and safe routinely. Okay. Let's dig into the 00:11:25.399 --> 00:11:27.360 clinical trial evidence a bit more, especially 00:11:27.360 --> 00:11:29.620 for weight loss. You mentioned some key studies. 00:11:29.759 --> 00:11:32.240 Yes. The review highlighted four major Phase 00:11:32.240 --> 00:11:37.519 III trials. Study 1839, 1922, 1923, and 3970. 00:11:37.899 --> 00:11:40.340 These were large, well -conducted studies. What 00:11:40.340 --> 00:11:43.360 were the key features? They were all randomized, 00:11:43.639 --> 00:11:46.659 double -blind, placebo -controlled, multi -center, 00:11:47.200 --> 00:11:50.679 The gold standard, really, involved over 5 ,000 00:11:50.679 --> 00:11:53.480 adults in total, conducted internationally, including 00:11:53.480 --> 00:11:55.559 Canada. And the main takeaway on weight loss. 00:11:55.899 --> 00:11:59.480 Across the board, Lear Glutide 3 mg led to significantly 00:11:59.480 --> 00:12:02.460 greater weight loss than placebo. This held true 00:12:02.460 --> 00:12:05.360 whether people had diabetes or not, had pre -diabetes, 00:12:05.779 --> 00:12:07.820 or even obstructive sleep apnea. And this was 00:12:07.820 --> 00:12:10.279 always compared against placebo plus lifestyle 00:12:10.279 --> 00:12:13.620 advice. Yes. Both groups got advice on diet and 00:12:13.620 --> 00:12:16.159 exercise. but the liraglutide group consistently 00:12:16.159 --> 00:12:18.100 lost more weight. And we're talking clinically 00:12:18.100 --> 00:12:21.019 meaningful amounts, not just a kilo or two. Definitely. 00:12:21.259 --> 00:12:23.600 The odds of achieving at least a 5 % weight loss 00:12:23.600 --> 00:12:26.580 and also more than 10 % weight loss were significantly 00:12:26.580 --> 00:12:28.480 higher with liraglutide compared to placebo. 00:12:28.679 --> 00:12:30.679 Can you give an example, like how much more weight 00:12:30.679 --> 00:12:34.539 loss? Sure. In study 1839, after 56 weeks, the 00:12:34.539 --> 00:12:36.279 average weight loss in the liraglutide group 00:12:36.279 --> 00:12:39.340 was about 5 .6 kilograms more than in the placebo 00:12:39.340 --> 00:12:41.909 group. So a noticeable difference. How did it 00:12:41.909 --> 00:12:43.629 stack up against something like arelastat? Were 00:12:43.629 --> 00:12:46.090 there comparisons? There weren't many direct 00:12:46.090 --> 00:12:49.309 head -to -head trials, but network meta -analyses, 00:12:49.330 --> 00:12:52.070 which kind of compare treatments indirectly using 00:12:52.070 --> 00:12:54.990 common comparators like placebo, suggested lower 00:12:54.990 --> 00:12:57.169 glutide 3 milligram was better than orlastat 00:12:57.169 --> 00:12:59.649 for achieving that bigger target, like 10 % weight 00:12:59.649 --> 00:13:02.090 loss. OK, so potentially more effective in those 00:13:02.090 --> 00:13:04.690 analyses. Yes, greater weight loss over placebo 00:13:04.690 --> 00:13:06.909 compared to orlastat. However. There's always 00:13:06.909 --> 00:13:09.659 a however. Right. Those same analyses suggested 00:13:09.659 --> 00:13:12.519 people were more likely to stop liraglutide due 00:13:12.519 --> 00:13:15.360 to side effects compared to oralist death. Ah. 00:13:15.759 --> 00:13:18.480 So a trade -off perhaps between efficacy and 00:13:18.480 --> 00:13:21.120 tolerability for some people. It often is. Balancing 00:13:21.120 --> 00:13:23.279 how well it works with how well someone feels 00:13:23.279 --> 00:13:25.899 on it is key. Did the trials look at quality 00:13:25.899 --> 00:13:28.679 of life? Did losing weight with liraglutide make 00:13:28.679 --> 00:13:31.480 people feel better in broader terms? They did 00:13:31.480 --> 00:13:34.309 measure it. using questionnaires like the IWQOL 00:13:34.309 --> 00:13:36.350 light, which is specific to weight's impact on 00:13:36.350 --> 00:13:38.750 life quality. Yeah. There were some improvements 00:13:38.750 --> 00:13:41.029 seen in the lower glutide groups, but honestly, 00:13:41.190 --> 00:13:43.950 the results were a bit mixed. Sometimes the differences 00:13:43.950 --> 00:13:45.970 weren't statistically significant after they 00:13:45.970 --> 00:13:47.710 adjusted for all the comparisons being made. 00:13:47.929 --> 00:13:50.389 So not a clear home run on the quality of life 00:13:50.389 --> 00:13:52.730 measures. Not consistently. Across all studies 00:13:52.730 --> 00:13:55.129 and all measures, no. Results from more general 00:13:55.129 --> 00:13:58.980 scales like the SF -36 were also a bit inconsistent. 00:13:59.480 --> 00:14:01.720 It suggests weight loss and metabolic improvements 00:14:01.720 --> 00:14:04.559 don't automatically translate perfectly to these 00:14:04.559 --> 00:14:07.340 broader QL scores in trial settings. Interesting. 00:14:07.379 --> 00:14:10.279 What about lipids? Cholesterol? Triglycerides? 00:14:10.460 --> 00:14:12.879 Yeah, they track those. There were some statistically 00:14:12.879 --> 00:14:14.919 significant changes, especially triglycerides 00:14:14.919 --> 00:14:17.840 tended to improve. But our clinical expert source 00:14:17.840 --> 00:14:20.720 felt the changes seen in LDL cholesterol specifically 00:14:20.720 --> 00:14:23.120 weren't really large enough to be considered 00:14:23.120 --> 00:14:25.620 clinically meaningful on their own. Good point. 00:14:25.799 --> 00:14:28.139 Statistical significance versus clinical relevance. 00:14:28.779 --> 00:14:31.580 Now we have to acknowledge the newer GLP -1 drugs 00:14:31.580 --> 00:14:34.620 like semaglutide. How does the liraglutide compare 00:14:34.620 --> 00:14:36.860 there? Right. The landscape is evolving fast. 00:14:37.139 --> 00:14:39.559 There was a head -to -head trial comparing semaglutide 00:14:39.559 --> 00:14:43.379 2 .4 milligrams weekly. to liraglutide 3 mg daily. 00:14:43.639 --> 00:14:46.080 And the results? Semaglutide came out significantly 00:14:46.080 --> 00:14:49.019 ahead on weight loss. Average was about 15 .8 00:14:49.019 --> 00:14:52.820 % loss with semaglutide versus 6 .4 % with liraglutide 00:14:52.820 --> 00:14:55.460 at 68 weeks. Wow, that's a substantial difference. 00:14:55.899 --> 00:14:59.019 It is. Interestingly, the proportion reporting 00:14:59.019 --> 00:15:02.019 GI side effects was similar, but more people 00:15:02.019 --> 00:15:04.639 actually stopped taking liraglutide in that specific 00:15:04.639 --> 00:15:07.100 trial. for various reasons. Shows the progress 00:15:07.100 --> 00:15:09.580 being made in this drug class. You also mentioned 00:15:09.580 --> 00:15:12.139 an ICER report. What did they conclude about 00:15:12.139 --> 00:15:15.120 liraglutide's value? ICER, the Institute for 00:15:15.120 --> 00:15:17.779 Clinical and Economic Review, they do these assessments 00:15:17.779 --> 00:15:20.279 of clinical effectiveness and value. They compared 00:15:20.279 --> 00:15:24.039 Saxinda liraglutide to other obesity treatments, 00:15:24.220 --> 00:15:27.100 including the newer GLP -1s and older meds. Aiming 00:15:27.100 --> 00:15:29.440 for a comparative picture of benefits and costs. 00:15:29.679 --> 00:15:32.200 Exactly. Trying to provide context for decision 00:15:32.200 --> 00:15:34.279 -making about which treatments offer the best 00:15:34.279 --> 00:15:36.240 value for patients and the healthcare system. 00:15:36.419 --> 00:15:38.240 Okay, that covers the clinical picture well. 00:15:38.759 --> 00:15:41.059 Let's switch gears to how it works, the mechanism 00:15:41.059 --> 00:15:43.480 of action. What's liraglutide actually doing 00:15:43.480 --> 00:15:47.340 in the body? So at its core, it's a GLP -1 receptor 00:15:47.340 --> 00:15:49.919 agonist. It mimics the action of our natural 00:15:49.919 --> 00:15:53.240 GLP -1 hormone by binding to and activating the 00:15:53.240 --> 00:15:55.600 GLP -1 receptor. And these receptors are found 00:15:55.600 --> 00:15:58.019 in various places. Yes, key locations include 00:15:58.019 --> 00:15:59.919 the pancreas and the brain. Let's start with 00:15:59.919 --> 00:16:02.039 the pancreas. What happens there? Activating 00:16:02.039 --> 00:16:05.659 GLP -1 receptors on pancreatic beta cells stimulates 00:16:05.659 --> 00:16:08.019 them to release insulin. But as we mentioned, 00:16:08.299 --> 00:16:10.639 it's glucose dependent. Only when sugar is high. 00:16:10.840 --> 00:16:13.220 Right. So it helps lower blood sugar after meals, 00:16:13.220 --> 00:16:15.399 for instance, without driving it too low otherwise. 00:16:15.940 --> 00:16:18.340 It also suppresses glucagon release from alpha 00:16:18.340 --> 00:16:21.200 cells in the pancreas. The double whammy for 00:16:21.200 --> 00:16:23.320 glucose control we talked about. Exactly. Now 00:16:23.320 --> 00:16:25.139 in the brain. This is for the weight effect. 00:16:25.320 --> 00:16:28.419 Yes. GLP -1 receptors are present in brain regions 00:16:28.419 --> 00:16:31.059 that control appetite and satiety, that feeling 00:16:31.059 --> 00:16:33.360 of fullness. So activating those receptors tells 00:16:33.360 --> 00:16:35.360 your brain you're full. Essentially, yes. It 00:16:35.360 --> 00:16:38.100 promotes satiety, reduces hunger, and that leads 00:16:38.100 --> 00:16:41.179 to eating less, lower energy intake, and ultimately 00:16:41.179 --> 00:16:44.480 weight loss. So pancreas for sugar, brain for 00:16:44.480 --> 00:16:46.820 weight. Are there other potential brain effects 00:16:46.820 --> 00:16:49.340 being explored? There is ongoing research, yeah. 00:16:49.500 --> 00:16:51.740 Looking into potential neuromodulatory roles, 00:16:52.200 --> 00:16:55.039 could GLP -1 signaling affect things like neurodegenerative 00:16:55.039 --> 00:16:58.399 diseases, Alzheimer's, Parkinson's, maybe mood 00:16:58.399 --> 00:17:01.779 disorders, addiction? Wow, really broad potential. 00:17:01.879 --> 00:17:04.240 It is, but still very much in the research phase 00:17:04.240 --> 00:17:06.059 for those areas. There's a lot more investigation. 00:17:06.299 --> 00:17:08.380 What about the heart and blood vessels? I saw 00:17:08.380 --> 00:17:10.619 mentions of cardiovascular effect. Yes, this 00:17:10.619 --> 00:17:13.700 is a really important area. GLP -1 receptors 00:17:13.700 --> 00:17:16.460 are found on heart cells, blood vessel walls, 00:17:16.619 --> 00:17:19.720 immune cells, even in the kidneys. Suggesting 00:17:19.720 --> 00:17:22.519 multiple ways it could be protective. Potentially, 00:17:22.619 --> 00:17:25.599 yes. The mechanisms aren't fully mapped out, 00:17:25.779 --> 00:17:27.920 but several things seem to happen. Like what? 00:17:28.339 --> 00:17:31.079 Improving endothelial function. The health of 00:17:31.079 --> 00:17:34.259 the blood vessel lining. It seems to boost nitric 00:17:34.259 --> 00:17:36.539 oxide, which helps vessels relax. Better blood 00:17:36.539 --> 00:17:39.279 flow. Right. And it might inhibit endothelin 00:17:39.279 --> 00:17:42.359 1, which constricts vessels. There's also some 00:17:42.359 --> 00:17:44.920 animal data suggesting anti -atherogenic effects 00:17:44.920 --> 00:17:47.299 may be slowing down plaque buildup in arteries. 00:17:47.539 --> 00:17:49.339 Does this translate clinically? We mentioned 00:17:49.339 --> 00:17:51.660 blood pressure and lipids earlier. We do see 00:17:51.660 --> 00:17:53.940 those improvements in risk factors. Lower vasolic 00:17:53.940 --> 00:17:56.259 blood pressure better triglycerides. There's 00:17:56.259 --> 00:17:58.319 also a theory it might help heart muscle cells 00:17:58.319 --> 00:18:00.980 use energy more efficiently. But there was that 00:18:00.980 --> 00:18:04.180 point about heart rate. Yes. One consistent finding 00:18:04.180 --> 00:18:06.359 is a small increase in resting heart rate in 00:18:06.359 --> 00:18:09.500 some patients. The clinical significance of that 00:18:09.500 --> 00:18:12.160 long term is still debated and being studied. 00:18:12.400 --> 00:18:15.900 So, a complex picture with effects across multiple 00:18:15.900 --> 00:18:19.039 systems. Let's talk about how the body handles 00:18:19.039 --> 00:18:22.619 the drug itself. Pharmacokinetics, pharmacodynamics, 00:18:23.240 --> 00:18:25.920 how quickly is it absorbed? After you inject 00:18:25.920 --> 00:18:28.700 it subcutaneously, it's absorbed pretty slowly. 00:18:28.880 --> 00:18:31.140 Cake levels in the blood usually occur between 00:18:31.140 --> 00:18:33.619 8 and 12 hours later. And that slow absorption 00:18:33.619 --> 00:18:36.259 is part of why it lasts long? It contributes, 00:18:36.480 --> 00:18:39.299 yes. The bioavailability how much actually gets 00:18:39.299 --> 00:18:42.319 into circulation is estimated around 55%. Is 00:18:42.319 --> 00:18:44.779 that slow absorption related to the drug structure? 00:18:45.059 --> 00:18:47.940 Yes, partly. The lyric glutide molecules can 00:18:47.940 --> 00:18:50.799 actually clump together self -associate, at the 00:18:50.799 --> 00:18:53.079 injection site. These clumps then slowly break 00:18:53.079 --> 00:18:55.480 apart, releasing the drug gradually for absorption. 00:18:55.740 --> 00:18:57.299 Interesting. Once it's in the blood, where does 00:18:57.299 --> 00:18:59.440 it go? Does it spread everywhere? Not really. 00:18:59.480 --> 00:19:02.279 It binds very strongly to plasma proteins, mostly 00:19:02.279 --> 00:19:05.839 albumin over 98 % bound. Ah, back to the albumin 00:19:05.839 --> 00:19:08.420 binding. Exactly. And because it's so tightly 00:19:08.420 --> 00:19:10.559 bound, it mostly stays within the bloodstream. 00:19:10.619 --> 00:19:12.700 It doesn't distribute widely into other tissues. 00:19:12.900 --> 00:19:14.940 Okay, so it circulates bound to albumin. How 00:19:14.940 --> 00:19:16.910 does the body get rid of it eventually? It's 00:19:16.910 --> 00:19:20.069 broken down, metabolized, similarly to how the 00:19:20.069 --> 00:19:22.829 body breaks down large proteins. Enzymes like 00:19:22.829 --> 00:19:25.509 DBP -IV and NEP are involved. But slower than 00:19:25.509 --> 00:19:28.690 they break down natural GLP -1. Much slower because 00:19:28.690 --> 00:19:31.450 of the modifications made to liraglutide. The 00:19:31.450 --> 00:19:33.490 breakdown products are only found in tiny amounts 00:19:33.490 --> 00:19:35.589 and eventually it's completely degraded into 00:19:35.589 --> 00:19:38.470 amino acids. So it's not mainly cleared by the 00:19:38.470 --> 00:19:40.750 kidneys or liver directly sending the whole drug 00:19:40.750 --> 00:19:44.069 out? No. The main route is this metabolic degradation. 00:19:44.700 --> 00:19:47.380 very little unchanged drug shows up in urine 00:19:47.380 --> 00:19:50.259 or feces. The clearance rate is low, and the 00:19:50.259 --> 00:19:52.819 elimination half -life is long, around 13 hours. 00:19:52.960 --> 00:19:54.720 Then that 13 -hour half -life is what allows 00:19:54.720 --> 00:19:56.960 for the once -daily dosing. Precisely. It sticks 00:19:56.960 --> 00:20:00.099 around long enough. Understanding that PKPPP 00:20:00.099 --> 00:20:02.500 profile is definitely key for using it effectively. 00:20:03.099 --> 00:20:05.559 Okay, let's shift to manufacturing. Making this 00:20:05.559 --> 00:20:08.460 stuff must be complicated. It really is. Lyraglutide 00:20:08.460 --> 00:20:10.799 is a fairly large peptide with that fatty acid 00:20:10.799 --> 00:20:13.220 chain attached. Acetylated peptide synthesis 00:20:13.220 --> 00:20:15.680 is complex and generally expensive. Requires 00:20:15.680 --> 00:20:18.440 specialized expertise. Absolutely. Companies 00:20:18.440 --> 00:20:21.119 like Badgem, who are experts in peptide manufacturing, 00:20:21.480 --> 00:20:23.599 were key partners in figuring out how to produce 00:20:23.599 --> 00:20:26.759 it at scale. It highlights the role of these 00:20:26.759 --> 00:20:30.160 specialist CDMOs, contract development, and manufacturing 00:20:30.160 --> 00:20:32.480 organizations. So it's not like stamping out 00:20:32.480 --> 00:20:35.569 simple pills. Not at all. use fragment -based 00:20:35.569 --> 00:20:37.789 approaches, making smaller pieces of the peptide 00:20:37.789 --> 00:20:40.309 separately, then carefully linking them together 00:20:40.309 --> 00:20:43.730 and finally adding the fatty acid bit. Lots of 00:20:43.730 --> 00:20:46.269 precise steps and purification needed. Sounds 00:20:46.269 --> 00:20:48.730 very high -tech. Fits with the broader trend 00:20:48.730 --> 00:20:52.759 of more complex biologic drugs. Now, the regulatory 00:20:52.759 --> 00:20:55.240 side. We know it's approved, but what was the 00:20:55.240 --> 00:20:58.180 journey like? Any bumps? Well, it gained approvals 00:20:58.180 --> 00:21:00.740 initially as Victoza for diabetes, then Sexenda 00:21:00.740 --> 00:21:03.200 for weight management, through the standard regulatory 00:21:03.200 --> 00:21:05.319 processes in the U .S., Europe, and elsewhere. 00:21:06.019 --> 00:21:08.039 A big recent development was the FDA approval 00:21:08.039 --> 00:21:10.400 of the first generic liver glutide injection 00:21:10.400 --> 00:21:13.470 in December 2024. Generics usually mean better 00:21:13.470 --> 00:21:15.869 access and lower costs eventually. Typically, 00:21:16.109 --> 00:21:18.849 yes. However, the journey wasn't entirely smooth. 00:21:19.170 --> 00:21:21.509 There was a significant legal settlement in 2017. 00:21:21.869 --> 00:21:23.430 Right. You mentioned that. What was it about? 00:21:23.869 --> 00:21:27.470 Novo Nordisk paid about $58 .6 million to the 00:21:27.470 --> 00:21:29.849 U .S. government to settle allegations involving 00:21:29.849 --> 00:21:32.970 the False Claims Act and the Food, Drug and Cosmetic 00:21:32.970 --> 00:21:35.319 Act. What were they accused of? The main issue 00:21:35.319 --> 00:21:37.500 was around compliance with the FDA -required 00:21:37.500 --> 00:21:40.460 REMES program, that's Risk Evaluation and Mitigation 00:21:40.460 --> 00:21:43.640 Strategy for Fictosa, between 2010 and 2014. 00:21:43.740 --> 00:21:45.839 And the problem was? The government alleged that 00:21:45.839 --> 00:21:48.759 the company's sales reps were trained to downplay 00:21:48.759 --> 00:21:52.019 or obscure the risk of medullary thyroid carcinoma, 00:21:52.140 --> 00:21:55.000 MTC, which is a serious potential risk noted 00:21:55.000 --> 00:21:57.720 in the boxed warning and REMES materials. So 00:21:57.720 --> 00:22:00.079 basically allegations that the safety message 00:22:00.079 --> 00:22:02.740 wasn't being delivered properly to doctors. That 00:22:02.740 --> 00:22:04.839 was the core allegation. Things like telling 00:22:04.839 --> 00:22:07.759 doctors the MTC risk was just in rodents or easily 00:22:07.759 --> 00:22:10.240 treatable, which allegedly misrepresented the 00:22:10.240 --> 00:22:12.519 FDA approved warning. That's serious. Did the 00:22:12.519 --> 00:22:15.259 settlement cover anything else? Yes. It also 00:22:15.259 --> 00:22:17.759 resolved allegations of illegal off -label promotion 00:22:17.759 --> 00:22:20.099 marketing Victoza for uses it wasn't approved 00:22:20.099 --> 00:22:22.380 for at the time, like weight loss before Saxenda 00:22:22.380 --> 00:22:25.240 was approved or for type 1 diabetes. And Novo 00:22:25.240 --> 00:22:28.289 Nordisk's position. They denied wrongdoing, but 00:22:28.289 --> 00:22:30.269 agreed to the settlement to resolve the matter. 00:22:31.250 --> 00:22:33.410 It definitely underscores how critical, accurate 00:22:33.410 --> 00:22:36.150 risk communication is. Absolutely. And it's approved 00:22:36.150 --> 00:22:38.990 in Europe, too. Yes. The EMA approved Saxenda 00:22:38.990 --> 00:22:41.970 for weight management across Europe. Both Victoza 00:22:41.970 --> 00:22:45.029 and Saxenda are registered trademarks of Novo 00:22:45.029 --> 00:22:48.150 Nordisk. OK, let's talk economics. This strike 00:22:48.150 --> 00:22:49.650 has been around a while. It must have made a 00:22:49.650 --> 00:22:52.190 significant impact financially. Oh, definitely. 00:22:52.289 --> 00:22:55.289 It's been a major product for Novo Nordisk. Market 00:22:55.289 --> 00:22:57.990 reports consistently show a large market for 00:22:57.990 --> 00:23:00.349 liraglutide and project continued growth for 00:23:00.349 --> 00:23:02.369 this whole class of drugs. How is the market 00:23:02.369 --> 00:23:05.009 broken down? You can look at it by brand Victoza 00:23:05.009 --> 00:23:07.950 versus Xenda and by distribution channels like 00:23:07.950 --> 00:23:10.910 hospital pharmacies, retail, online pharmacies. 00:23:11.109 --> 00:23:13.450 And how does liraglutide fit into the bigger 00:23:13.450 --> 00:23:15.970 picture of the pharma market, especially diabetes 00:23:15.970 --> 00:23:18.710 and obesity? It's been a huge part of the massive 00:23:18.710 --> 00:23:21.369 growth in the GLP -1 agonist market overall. 00:23:21.549 --> 00:23:24.009 Some analysts compare the potential impact of 00:23:24.009 --> 00:23:26.529 these drugs on obesity to what statins did for 00:23:26.529 --> 00:23:29.230 heart disease. A potential game changer. That's 00:23:29.230 --> 00:23:32.009 the view. There's a strong belief that GLP -1s 00:23:32.009 --> 00:23:34.990 are becoming, and will continue to be, a major 00:23:34.990 --> 00:23:38.190 force in healthcare economics and treatment paradigms. 00:23:38.369 --> 00:23:40.750 Fascinating how science translates to market 00:23:40.750 --> 00:23:44.089 forces. Lastly, let's touch on the cultural side. 00:23:44.410 --> 00:23:47.650 How are drugs like liraglutide influencing how 00:23:47.650 --> 00:23:50.269 we think about weight? It's complicated, really. 00:23:50.650 --> 00:23:53.069 On one hand, having effective medical treatments 00:23:53.069 --> 00:23:55.670 could help shift the view of obesity away from 00:23:55.670 --> 00:23:58.029 being just a matter of willpower. Towards seeing 00:23:58.029 --> 00:24:00.730 it more as a treatable medical condition. Exactly. 00:24:01.230 --> 00:24:02.990 That could potentially reduce weight stigma, 00:24:03.170 --> 00:24:05.130 which is a huge problem. But there's a potential 00:24:05.130 --> 00:24:08.509 downside. Yes. Access is a big issue. These drugs 00:24:08.509 --> 00:24:11.250 are expensive. Insurance coverage varies wildly. 00:24:11.710 --> 00:24:14.640 So... There's a risk it could actually worsen 00:24:14.640 --> 00:24:17.160 stigma if only wealthier people can access them, 00:24:17.559 --> 00:24:19.299 creating a kind of bias against those who can't 00:24:19.299 --> 00:24:21.799 afford treatment. A potential new layer of inequality. 00:24:22.259 --> 00:24:24.579 Potentially. And there's also the idea mentioned 00:24:24.579 --> 00:24:26.500 in some sources that people using these drugs 00:24:26.500 --> 00:24:29.119 might face stigma for taking the easy way out, 00:24:29.400 --> 00:24:31.119 similar to negative attitudes sometimes seen 00:24:31.119 --> 00:24:33.319 towards bariatric surgery patients. So we need 00:24:33.319 --> 00:24:35.960 to be really careful about access and messaging. 00:24:36.440 --> 00:24:39.119 Patient groups often report facing stigma already, 00:24:39.319 --> 00:24:41.980 right? Absolutely. Significant social stigma 00:24:41.980 --> 00:24:44.599 exists. impacting everything from employment 00:24:44.599 --> 00:24:47.720 to healthcare interactions. People report feeling 00:24:47.720 --> 00:24:50.339 shamed by doctors, sometimes avoiding care altogether. 00:24:51.000 --> 00:24:52.980 There's still this pervasive misunderstanding 00:24:52.980 --> 00:24:55.960 of obesity as purely self -inflicted. It's a 00:24:55.960 --> 00:24:58.859 really complex intersection of medicine and societal 00:24:58.859 --> 00:25:01.259 views. Okay, we've covered so much. Before we 00:25:01.259 --> 00:25:03.680 wrap up, let's quickly hit the key safety points 00:25:03.680 --> 00:25:06.319 for liraglutide. Right. Most common side effects 00:25:06.319 --> 00:25:09.940 are GI issues. Nausea is very frequent, especially 00:25:09.940 --> 00:25:12.920 when starting or increasing the dose. Vomiting, 00:25:13.220 --> 00:25:15.380 diarrhea, constipation can also happen. Those 00:25:15.380 --> 00:25:17.680 are the common ones. What about more serious 00:25:17.680 --> 00:25:20.579 potential risks? Hypoglycemia, low blood sugar 00:25:20.579 --> 00:25:23.160 is a risk, but mainly when it's used with other 00:25:23.160 --> 00:25:25.839 drugs that also lower sugar, like sulfonylureas 00:25:25.839 --> 00:25:28.759 or insulin. Dose adjustments might be needed 00:25:28.759 --> 00:25:31.519 then. What else? That increase in resting heart 00:25:31.519 --> 00:25:34.180 rate we mentioned needs monitoring. There have 00:25:34.180 --> 00:25:36.599 been post -marketing reports of kidney problems. 00:25:36.779 --> 00:25:39.359 sometimes linked to dehydration from the GI side 00:25:39.359 --> 00:25:42.720 effects, and hypersensitivity reactions, though 00:25:42.720 --> 00:25:45.859 rare, can occur. So monitoring is key, especially 00:25:45.859 --> 00:25:48.539 kidney function, if someone has bad GI side effects. 00:25:48.880 --> 00:25:51.140 Definitely. Patients need to know the signs of 00:25:51.140 --> 00:25:54.039 hypoglycemia, too. And doctors need to be cautious 00:25:54.039 --> 00:25:56.200 with patients who already have kidney issues. 00:25:57.039 --> 00:25:59.019 All the details are in the official warnings. 00:25:59.259 --> 00:26:01.440 What about the pancreatitis concerns that came 00:26:01.440 --> 00:26:04.059 up early with GLP -1 drugs? That's a good point. 00:26:04.619 --> 00:26:06.839 There were initial concerns based on other drugs 00:26:06.839 --> 00:26:10.259 in the class, but specific large animal safety 00:26:10.259 --> 00:26:13.440 studies on liraglutide in rats, mice, monkeys 00:26:13.440 --> 00:26:15.920 didn't find evidence of pancreatitis at clinically 00:26:15.920 --> 00:26:18.559 relevant doses. That was reassuring. Good to 00:26:18.559 --> 00:26:20.599 know. Well, this has certainly been a comprehensive 00:26:20.599 --> 00:26:23.460 deep dive. It really has. We've traced liraglutide 00:26:23.460 --> 00:26:25.619 from those early in cretin discoveries all the 00:26:25.619 --> 00:26:27.640 way to what's used today for diabetes and obesity. 00:26:27.869 --> 00:26:30.170 We've looked at how it works, how the body handles 00:26:30.170 --> 00:26:33.289 it, manufacturing, the regulatory path, economic 00:26:33.289 --> 00:26:35.369 impact, and even how it intersects with cultural 00:26:35.369 --> 00:26:37.490 views on weight. And it's clear that while it 00:26:37.490 --> 00:26:39.890 offers real benefits, there are important things 00:26:39.890 --> 00:26:43.210 to consider side effects, access issues, societal 00:26:43.210 --> 00:26:46.250 perceptions. Absolutely. Which leads us to a 00:26:46.250 --> 00:26:48.890 final thought for you, our listener, to maul 00:26:48.890 --> 00:26:51.710 over. As these kinds of medications become more 00:26:51.710 --> 00:26:54.240 common, How is our whole approach to chronic 00:26:54.240 --> 00:26:57.359 conditions like obesity and type 2 diabetes going 00:26:57.359 --> 00:27:00.019 to change? What are the bigger societal questions 00:27:00.019 --> 00:27:02.480 we really need to grapple with? A really important 00:27:02.480 --> 00:27:04.660 question. We hope this discussion gave you a 00:27:04.660 --> 00:27:06.980 solid foundation. We definitely encourage you 00:27:06.980 --> 00:27:09.079 to explore the sources and keep thinking about 00:27:09.079 --> 00:27:11.700 this interception of science, medicine, and society. 00:27:12.400 --> 00:27:13.779 Thanks for joining us on the Deep Dive.