WEBVTT 00:00:00.000 --> 00:00:02.540 Welcome to the deep dive. This is where we take 00:00:02.540 --> 00:00:05.099 the sources you send us, jump right in and pull 00:00:05.099 --> 00:00:07.440 out the key stuff, those aha moments you're looking 00:00:07.440 --> 00:00:10.240 for. Yeah, making sense of complex topics fast. 00:00:10.400 --> 00:00:13.960 Exactly. And today we're focusing on a medication 00:00:13.960 --> 00:00:18.160 many people know or use. Citagliptin. You probably 00:00:18.160 --> 00:00:20.839 know it as Genuvia, maybe Genumet. That's right. 00:00:20.920 --> 00:00:24.679 We've gone through a lot of material clinical 00:00:24.679 --> 00:00:28.079 studies, regulatory docs, market reports, to 00:00:28.079 --> 00:00:30.260 really get a handle on this drug. Our listener, 00:00:30.780 --> 00:00:33.600 the learner, this you, someone curious, wanting 00:00:33.600 --> 00:00:37.380 the knowledge without drowning in data, ask us 00:00:37.380 --> 00:00:39.439 to unpack Citagliptin. And we're ready to do 00:00:39.439 --> 00:00:41.240 that. We'll look at its history, how it works, 00:00:41.399 --> 00:00:43.579 its uses, how it's made, the rules around it, 00:00:44.020 --> 00:00:46.439 and, well, the impact it's had. Okay, let's dive 00:00:46.439 --> 00:00:49.240 in. Where did Citagliptin even come from? Well, 00:00:49.380 --> 00:00:51.539 this story really kicks off back in the 1990s. 00:00:52.060 --> 00:00:54.119 Scientists made a really key discovery. Oh, yeah. 00:00:54.240 --> 00:00:56.500 What was that? They figured out that an enzyme 00:00:56.500 --> 00:01:00.780 called dipeptidylpepsidase 4, or DPP4 for short, 00:01:01.219 --> 00:01:03.140 was responsible for shutting down these hormones 00:01:03.140 --> 00:01:05.939 called incretins. Incretins, like GLP1, I've 00:01:05.939 --> 00:01:08.939 heard of that one. Exactly. GLP1 and another 00:01:08.939 --> 00:01:11.379 one called GIP. These are super important for 00:01:11.379 --> 00:01:13.719 managing blood sugar. Think of them as signals. 00:01:13.879 --> 00:01:15.939 It signals. Yeah, they tell your pancreas, hey, 00:01:16.079 --> 00:01:18.459 release some insulin, blood sugar's up. And they 00:01:18.459 --> 00:01:21.980 also tell your liver to maybe chill out on making 00:01:21.980 --> 00:01:25.640 more glucose. OK, so DPP4 stops these helpful 00:01:25.640 --> 00:01:28.540 signals. Pretty much. It inactivates them. So 00:01:28.540 --> 00:01:31.120 the thinking was, what if we could stop DPP4 00:01:31.120 --> 00:01:33.659 from doing that? Could we keep those encretins 00:01:33.659 --> 00:01:36.859 working longer? Ah, I see. the light bulb moment, 00:01:37.079 --> 00:01:40.000 keep the good hormones active. Precisely. And 00:01:40.000 --> 00:01:42.760 that led to the idea of DPP4 inhibitors drugs 00:01:42.760 --> 00:01:44.879 designed to block that enzyme. Cidagliptin was 00:01:44.879 --> 00:01:46.480 one of the first ones developed that you could 00:01:46.480 --> 00:01:49.099 just take as a pill. Sounds great for now, but 00:01:49.099 --> 00:01:51.280 I bet it wasn't quick. Oh, definitely not. Our 00:01:51.280 --> 00:01:53.640 sources highlight that. turning that basic science 00:01:53.640 --> 00:01:56.659 into an actual medicine that takes years. Lots 00:01:56.659 --> 00:01:58.659 of research collaboration between universities 00:01:58.659 --> 00:02:01.299 and drug companies, persistence. It's a long 00:02:01.299 --> 00:02:03.799 road. Right. Citigliptin and others like it finally 00:02:03.799 --> 00:02:07.219 got regulatory approval and hit the market, mostly 00:02:07.219 --> 00:02:10.580 between 2006 and 2013. OK, so that's the why. 00:02:11.259 --> 00:02:13.680 Now, for the learner out there, maybe taking 00:02:13.680 --> 00:02:16.139 it or knowing someone who does. Yeah. How does 00:02:16.139 --> 00:02:19.240 it actually work? So at its core, it does exactly 00:02:19.240 --> 00:02:22.370 what we just talked about. It slows down that 00:02:22.370 --> 00:02:32.469 DPC4 enzyme. By inhibiting it. Yes. Stay active 00:02:32.469 --> 00:02:34.270 longer. And what does that do for blood sugar? 00:02:34.490 --> 00:02:37.449 It has a really neat dual effect. First, higher 00:02:37.449 --> 00:02:40.490 levels of active GLP -1 and GIP mean more insulin 00:02:40.490 --> 00:02:43.669 release from the pancreas. But, and this is important, 00:02:44.169 --> 00:02:48.000 it's glucose dependent, meaning It mostly ramps 00:02:48.000 --> 00:02:50.120 up insulin release when your blood sugar is actually 00:02:50.120 --> 00:02:52.120 high. It's not just pushing insulin out all the 00:02:52.120 --> 00:02:54.520 time. OK. That sounds smart. Prevent lows, maybe? 00:02:54.599 --> 00:02:56.879 That's a big part of it. The second effect is 00:02:56.879 --> 00:02:59.580 it lowers glucagon secretion. Glucagon is the 00:02:59.580 --> 00:03:01.699 hormone that tells the liver to make more glucose. 00:03:01.979 --> 00:03:04.500 So less glucagon means less glucose production 00:03:04.500 --> 00:03:06.620 from the liver. Got it. So smarter insulin release, 00:03:06.840 --> 00:03:08.879 less liver glucose. Makes sense. You mentioned 00:03:08.879 --> 00:03:11.800 selectivity earlier. Right. At the usual doses, 00:03:11.960 --> 00:03:14.419 citaglyptin is much better at targeting DPP4 00:03:14.419 --> 00:03:17.939 than some related enzymes, like DPP8 or DPP9. 00:03:18.360 --> 00:03:20.259 That selectivity is thought to help with its 00:03:20.259 --> 00:03:22.789 safety profile. And the low blood sugar thing, 00:03:22.969 --> 00:03:25.349 hypoglycemia. Yeah, that's a key point. On its 00:03:25.349 --> 00:03:28.830 own, cytaglyptin has a low risk of causing hypoglycemia 00:03:28.830 --> 00:03:31.150 because its action is tied to glucose levels. 00:03:31.289 --> 00:03:33.430 Now if you take it with something like a sulfonylurea 00:03:33.430 --> 00:03:35.610 or insulin... Then the risk goes up. Then the 00:03:35.610 --> 00:03:38.250 risk can increase, yes. Because those other drugs 00:03:38.250 --> 00:03:41.120 can lower blood sugar independently, so... Doctors 00:03:41.120 --> 00:03:43.460 might need to lower the dose of the sulfonylurea 00:03:43.460 --> 00:03:46.080 or insulin in that case. Makes sense. And interestingly, 00:03:46.219 --> 00:03:48.199 when you take it with metformin, another really 00:03:48.199 --> 00:03:50.740 common diabetes drug, studies show it actually 00:03:50.740 --> 00:03:53.580 boosts the levels of active GLP -1 even more, 00:03:53.740 --> 00:03:56.719 an additive effect. Huh. Anything else on how 00:03:56.719 --> 00:03:58.819 it works? What about the heart checks? Oh, right. 00:03:58.819 --> 00:04:01.360 The ECG studies. They looked at the heart's electrical 00:04:01.360 --> 00:04:04.439 rhythm, specifically the QTC interval, and found 00:04:04.439 --> 00:04:06.699 no significant changes at therapeutic doses. 00:04:06.960 --> 00:04:09.360 That was important for safety assessment. Good 00:04:09.360 --> 00:04:11.879 to know. Okay, so we understand how it works. 00:04:12.180 --> 00:04:14.259 What happens in the body after someone swallows 00:04:14.259 --> 00:04:17.329 the pill? The pharmacokinetics. Right, how the 00:04:17.329 --> 00:04:19.410 body handles it. Well, it gets absorbed pretty 00:04:19.410 --> 00:04:21.529 quickly. You usually see peak levels in the blood 00:04:21.529 --> 00:04:24.009 within about, say, one to four hours. Does food 00:04:24.009 --> 00:04:27.329 affect it much? Not really significantly. Maybe 00:04:27.329 --> 00:04:29.709 slows absorption just a tiny bit, but the overall 00:04:29.709 --> 00:04:32.329 amount absorbed is similar. Studies in healthy 00:04:32.329 --> 00:04:34.629 folks give us numbers, like a 100 -milligram 00:04:34.629 --> 00:04:38.370 dose gives a total exposure, the AUC around 8 00:04:38.370 --> 00:04:42.689 .5 micromolar hour, peak level around 950 nanomolar. 00:04:42.850 --> 00:04:44.730 And the half -life. How long does it stick around? 00:04:44.939 --> 00:04:48.339 The half -life is about 12 .4 hours. Ah, okay. 00:04:48.560 --> 00:04:50.399 That explains the typical one -to -day dosing. 00:04:50.699 --> 00:04:52.660 Exactly. And the more you take, the higher the 00:04:52.660 --> 00:04:55.420 levels, pretty much dose proportionally. It also 00:04:55.420 --> 00:04:57.639 seems the body handles it similarly whether you're 00:04:57.639 --> 00:04:59.839 healthy or have type 2 diabetes. How does the 00:04:59.839 --> 00:05:02.399 body get rid of it? Metabolism? Excretion? It's 00:05:02.399 --> 00:05:04.740 not heavily metabolized, actually. Some breakdown 00:05:04.740 --> 00:05:09.279 happens via liver enzymes. CYP3A4 and CYP2C8 00:05:09.279 --> 00:05:11.339 are the main ones, but it's limited. So mostly. 00:05:11.519 --> 00:05:13.560 Mostly it's cleared out by the kidneys. About 00:05:13.560 --> 00:05:16.600 87 % of the dose comes out in the urine, largely 00:05:16.600 --> 00:05:19.399 unchanged. It uses active transport systems in 00:05:19.399 --> 00:05:21.860 the kidneys to get there. Okay, kidneys. That 00:05:21.860 --> 00:05:23.759 sounds critical for people with kidney problems. 00:05:24.000 --> 00:05:25.740 Absolutely critical. If your kidney function 00:05:25.740 --> 00:05:28.579 is reduced, the drug can build up, so dose adjustments 00:05:28.579 --> 00:05:30.500 are really important. How do they figure that 00:05:30.500 --> 00:05:33.519 out? Based on kidney function tests, specifically 00:05:33.519 --> 00:05:36.879 the EGFR estimated glomerular filtration rate. 00:05:37.069 --> 00:05:40.350 There are specific guidelines. If your EGFR is 00:05:40.350 --> 00:05:43.870 say between 30 and 45, the dose is usually half 00:05:43.870 --> 00:05:47.029 to 50 milligram daily. And if it's lower? Below 00:05:47.029 --> 00:05:49.769 30 or if someone's on dialysis, the dose typically 00:05:49.769 --> 00:05:53.410 drops to 25 milligrams daily. It's worth noting, 00:05:53.649 --> 00:05:55.970 dialysis does remove some sitagliptin, maybe 00:05:55.970 --> 00:05:58.730 around 13 .5 % in a typical session, but the 00:05:58.730 --> 00:06:01.110 lower daily dose is still needed. Really crucial 00:06:01.110 --> 00:06:03.670 info for doctors and patients. Okay, let's switch 00:06:03.670 --> 00:06:06.250 gears to how it's actually used. Clinical applications. 00:06:06.490 --> 00:06:08.709 Its main job is helping control blood sugar in 00:06:08.709 --> 00:06:11.509 adults with type 2 diabetes, alongside diet and 00:06:11.509 --> 00:06:13.509 exercise, of course. And you take it by itself. 00:06:13.740 --> 00:06:17.579 You can, yes, as monotherapy if lifestyle changes 00:06:17.579 --> 00:06:20.319 aren't enough. But honestly, it's very often 00:06:20.319 --> 00:06:22.639 used in combination with other diabetes meds. 00:06:22.839 --> 00:06:25.439 Like Metformin. Metformin is a very common partner, 00:06:26.100 --> 00:06:29.759 but also sulfonylerias, pioglitazone, even insulin. 00:06:30.379 --> 00:06:32.860 The goal is better overall glucose control. And 00:06:32.860 --> 00:06:34.319 does it work well? What do the studies show? 00:06:34.439 --> 00:06:37.100 Yeah, clinical trials consistently show it lowers 00:06:37.100 --> 00:06:40.000 HbA1c, which is that key measure of long -term 00:06:40.000 --> 00:06:42.740 blood sugar control. How much? As monotherapy, 00:06:43.079 --> 00:06:47.259 usually around 0 .5 % to 1 .0 % reduction. Added 00:06:47.259 --> 00:06:49.740 cement formin, maybe a bit more, like 0 .6 % 00:06:49.740 --> 00:06:53.220 to 1 .1%. And interestingly, people starting 00:06:53.220 --> 00:06:55.959 with higher A1c levels tend to see a bigger drop. 00:06:56.120 --> 00:06:58.240 Does it help with both fasting and after meal 00:06:58.240 --> 00:07:00.920 sugar? Yes, it helps lower both fasting glucose 00:07:00.920 --> 00:07:03.139 and those post meal spikes. What about weight? 00:07:03.720 --> 00:07:05.839 is a concern with diabetes meds. That's actually 00:07:05.839 --> 00:07:07.879 one of Cytagliptin's selling points. It's generally 00:07:07.879 --> 00:07:10.199 weight neutral. Meaning it doesn't cause weight 00:07:10.199 --> 00:07:14.459 gain? Right. Unlike some older drugs like sulfonylureas 00:07:14.459 --> 00:07:17.319 or TZDs, which often cause weight gain. Now, 00:07:17.319 --> 00:07:19.480 it's also different from some newer classes like 00:07:19.480 --> 00:07:22.899 GLP -1 agonists or SGLT -2 inhibitors, which 00:07:22.899 --> 00:07:25.899 can actually lead to weight loss. But for many, 00:07:26.360 --> 00:07:29.240 just not gaining weight is a win. Yeah, definitely. 00:07:29.839 --> 00:07:32.930 So low hypoglycemia risk when used alone. weight 00:07:32.930 --> 00:07:36.629 neutral. Sounds pretty good. How well do people 00:07:36.629 --> 00:07:39.069 tolerate it generally? Generally well tolerated 00:07:39.069 --> 00:07:41.709 in trials across different ages and BMIs. There 00:07:41.709 --> 00:07:43.889 was even a study looking specifically at patients 00:07:43.889 --> 00:07:46.029 with mild kidney problems. Oh, yeah. Compared 00:07:46.029 --> 00:07:49.290 to another drug, Dapaglucin, Citagliptin actually 00:07:49.290 --> 00:07:51.250 showed better glycemic control in that group 00:07:51.250 --> 00:07:53.370 and was still well tolerated. Interesting. And 00:07:53.370 --> 00:07:56.110 adding it to metformin and insulin, studies showed 00:07:56.110 --> 00:07:59.410 that combo led to significantly better A1C reductions 00:07:59.410 --> 00:08:02.189 and helped more people reach that target A1C 00:08:02.189 --> 00:08:04.410 of less than 7%. OK, that paints a good picture 00:08:04.410 --> 00:08:06.670 of its use. Now, a quick look behind the scenes. 00:08:06.990 --> 00:08:09.129 How do they actually make this stuff? Manufacturing. 00:08:09.230 --> 00:08:11.230 It's evolved over time, become more efficient. 00:08:11.629 --> 00:08:13.790 The current main process involves basically three 00:08:13.790 --> 00:08:16.949 key chemical steps. Well, three main transformations. 00:08:17.649 --> 00:08:20.870 First, forming something called an enamine. Then, 00:08:21.269 --> 00:08:24.750 the really crucial step, asymmetric hydrogenation. 00:08:24.870 --> 00:08:27.439 Sounds complex. It uses a special catalyst to 00:08:27.439 --> 00:08:29.779 make sure the molecule has the exact right 3D 00:08:29.779 --> 00:08:32.039 shape. That shape is vital for it to work in 00:08:32.039 --> 00:08:34.039 the body. It's very selective, makes the right 00:08:34.039 --> 00:08:35.919 version. They're over chemistry. Yeah, and they've 00:08:35.919 --> 00:08:38.019 figured out how to recycle a lot of that expensive 00:08:38.019 --> 00:08:40.879 catalyst, which is good for costs and, you know, 00:08:41.179 --> 00:08:43.500 sustainability. The final step is turning it 00:08:43.500 --> 00:08:45.980 into a stable phosphate salt. That's what's in 00:08:45.980 --> 00:08:48.460 the pill. Fascinating. OK, let's talk regulation. 00:08:48.960 --> 00:08:53.120 Approvals, safety issues, legal stuff. What's 00:08:53.120 --> 00:08:55.149 the story there? It got the green light from 00:08:55.149 --> 00:08:57.730 major agencies like the FDA in the US back in 00:08:57.730 --> 00:09:01.570 2006 and the EMA in Europe. And like all drugs, 00:09:01.649 --> 00:09:03.669 it's been watched closely ever since it hit the 00:09:03.669 --> 00:09:05.409 market post -marketing surveillance. Keeping 00:09:05.409 --> 00:09:07.610 an eye out for problems. Exactly. Looking at 00:09:07.610 --> 00:09:09.710 safety and effectiveness in the real world over 00:09:09.710 --> 00:09:12.110 the long term. Studies in Japan, for instance, 00:09:12.190 --> 00:09:14.809 have provided good long -term data. Have there 00:09:14.809 --> 00:09:17.210 been any significant safety flags or controversies? 00:09:17.429 --> 00:09:19.529 Yes, there have been a few things over the years. 00:09:19.870 --> 00:09:22.269 Pancreatitis was one of the early ones. Inflammation 00:09:22.269 --> 00:09:24.600 of the pancreas. Right. There were reports after 00:09:24.600 --> 00:09:27.559 it launched, including some serious cases. FDA 00:09:27.559 --> 00:09:30.279 analysis suggested maybe a higher reporting rate 00:09:30.279 --> 00:09:32.480 compared to some other drugs. Did the big trials 00:09:32.480 --> 00:09:35.320 confirm that? The big TACOS trial that was its 00:09:35.320 --> 00:09:38.700 cardiovascular safety study didn't find a statistically 00:09:38.700 --> 00:09:41.299 significant increase with cytagliptin itself. 00:09:42.299 --> 00:09:46.100 But looking at the whole class of DPP4 inhibitors 00:09:46.100 --> 00:09:49.139 together, a meta -analysis did suggest a small 00:09:49.139 --> 00:09:51.299 increased risk. So what's the situation now? 00:09:51.980 --> 00:09:54.600 There are warnings about pancreatitis on the 00:09:54.600 --> 00:09:57.279 label. Doctors are told to stop the drug if it's 00:09:57.279 --> 00:10:00.440 suspected. Any other major concerns? Pancreatic 00:10:00.440 --> 00:10:02.360 cancer was mentioned sometimes. Yeah, that came 00:10:02.360 --> 00:10:04.659 up partly linked to the pancreatitis concerns. 00:10:04.759 --> 00:10:07.100 But again, the TACOS trial actually had slightly 00:10:07.100 --> 00:10:09.139 fewer cases in the cytogliptin group, though 00:10:09.139 --> 00:10:11.899 not statistically significant. And bigger analyses 00:10:11.899 --> 00:10:14.139 haven't found a clear link, but, you know, they 00:10:14.139 --> 00:10:16.120 keep monitoring. What about heart failure? That's 00:10:16.120 --> 00:10:18.850 been an issue for some diabetes drugs. It has. 00:10:19.269 --> 00:10:21.789 Some other DP3 -4 inhibitors did show an increased 00:10:21.789 --> 00:10:24.690 risk in their big trials. But the TECOS trial, 00:10:25.049 --> 00:10:27.570 specifically for citagliptin, did not find an 00:10:27.570 --> 00:10:30.230 increased risk of hospitalization for heart failure. 00:10:30.409 --> 00:10:32.309 OK, that's reassuring for citagliptin itself. 00:10:32.529 --> 00:10:35.509 It is. But the label still advises caution, telling 00:10:35.509 --> 00:10:37.750 doctors to weigh risks and benefits in patients 00:10:37.750 --> 00:10:40.309 who already have heart failure risk factors. 00:10:40.529 --> 00:10:43.200 Makes sense to be cautious. Anything else? A 00:10:43.200 --> 00:10:45.320 few other things flagged by regulators based 00:10:45.320 --> 00:10:48.799 on post -marketing reports. Severe joint panarthralgia. 00:10:49.120 --> 00:10:51.860 The FDA noted this could happen with any DPP4 00:10:51.860 --> 00:10:53.799 inhibitor. Usually goes away if you stop the 00:10:53.799 --> 00:10:57.019 drug. Ouch. Also, a rare autoimmune skin condition 00:10:57.019 --> 00:11:00.340 called bullis pemphigoid. Reports led to label 00:11:00.340 --> 00:11:03.480 warnings. Serious allergic reactions, hypersensitivity 00:11:03.480 --> 00:11:06.059 have also been reported. And kidney issues. Acute 00:11:06.059 --> 00:11:08.500 kidney problems, sometimes needing dialysis, 00:11:08.639 --> 00:11:10.480 were reported, especially in people who already 00:11:10.480 --> 00:11:13.620 had kidney issues and weren't on the right. Adjusted 00:11:13.620 --> 00:11:15.879 dose. Underscores the importance of correct dosing 00:11:15.879 --> 00:11:18.399 we talked about earlier. Absolutely. And more 00:11:18.399 --> 00:11:22.419 recently, in 2022, there was the issue with NTTP, 00:11:22.500 --> 00:11:25.000 a type of nitrosamine empiric - found in some 00:11:25.000 --> 00:11:27.399 batches. I remember hearing about nitrosamines 00:11:27.399 --> 00:11:29.620 in other drugs too. Yeah, it's been an issue 00:11:29.620 --> 00:11:32.100 across the industry. Health authorities assessed 00:11:32.100 --> 00:11:34.600 the immediate risk as low, but allowed slightly 00:11:34.600 --> 00:11:37.399 higher temporary limits to avoid shortages, while 00:11:37.399 --> 00:11:39.600 the manufacturer fixed the process to meet the 00:11:39.600 --> 00:11:42.139 strict long -term limits. Quite a regulatory 00:11:42.139 --> 00:11:44.470 journey. What about patents and generics? That 00:11:44.470 --> 00:11:47.110 must be a big factor now. Huge factor. The main 00:11:47.110 --> 00:11:49.570 patent on the Cytaglyptan molecule itself actually 00:11:49.570 --> 00:11:53.190 expired in the U .S. in January 2023. So generics 00:11:53.190 --> 00:11:55.830 should be everywhere now. Well, not quite in 00:11:55.830 --> 00:11:58.289 the U .S. Merck, the original maker, has another 00:11:58.289 --> 00:12:00.789 patent on the specific phosphate salt form used 00:12:00.789 --> 00:12:03.519 in Genuvia and Janumet. And through lawsuits 00:12:03.519 --> 00:12:05.899 and settlements, they've managed to keep exclusivity 00:12:05.899 --> 00:12:10.000 for those brands until May 2026 in the U .S. 00:12:10.320 --> 00:12:14.580 Janumet XR lasts until July 2026. Interesting. 00:12:14.779 --> 00:12:17.100 So a later patent is keeping the generics at 00:12:17.100 --> 00:12:19.639 bay for a bit longer there. Essentially, yes. 00:12:19.840 --> 00:12:21.740 Though the FDA has approved a generic version, 00:12:22.019 --> 00:12:23.860 it's one that pharmacists can't automatically 00:12:23.860 --> 00:12:26.639 substitute. Merck themselves expect price and 00:12:26.639 --> 00:12:29.500 volume to drop in the U .S. during 2024 as that 00:12:29.500 --> 00:12:32.000 date gets closer. What about outside the U .S.? 00:12:32.000 --> 00:12:34.259 Different story. Generic Citiglipton has been 00:12:34.259 --> 00:12:37.460 available in Europe since late 2021, early 2022. 00:12:38.320 --> 00:12:40.960 And competition is happening in China, too. That's 00:12:40.960 --> 00:12:42.860 definitely hitting the branded sales in those 00:12:42.860 --> 00:12:45.139 regions. Which leads us straight to the economic 00:12:45.139 --> 00:12:47.440 impact. It sounds like Genuvia Janumet was a 00:12:47.440 --> 00:12:49.679 massive product for Merck. Oh, absolutely. A 00:12:49.679 --> 00:12:52.059 true blockbuster. It was their top selling drug 00:12:52.059 --> 00:12:54.899 for a while. Peak sales for the franchise were 00:12:54.899 --> 00:13:00.539 around $9 .2 billion globally in 2020. Wow. But 00:13:00.539 --> 00:13:03.200 declining now. Yeah, the trend is downward, still 00:13:03.200 --> 00:13:06.700 significant revenue, like $3 .4 billion in 2023, 00:13:06.799 --> 00:13:09.340 but definitely declining. And that's mostly down 00:13:09.340 --> 00:13:11.679 to the patent explorations and generic competition. 00:13:11.840 --> 00:13:13.940 That's the main driver, especially where generics 00:13:13.940 --> 00:13:16.320 are already launched, but also increasing competition 00:13:16.320 --> 00:13:19.179 from newer diabetes drug classes, general pricing 00:13:19.179 --> 00:13:21.860 pressures. Maybe the nitrosamine issue had some 00:13:21.860 --> 00:13:23.860 small impact, too. But the U .S. market is still 00:13:23.860 --> 00:13:26.460 holding up relatively well because of that extended 00:13:26.460 --> 00:13:29.580 patent protection. For now, yes, that U .S. market 00:13:29.610 --> 00:13:31.889 is crucial for its remaining sales, though even 00:13:31.889 --> 00:13:33.970 there, as we said, they expect erosion. We also 00:13:33.970 --> 00:13:36.309 see different trends regionally, like sales are 00:13:36.309 --> 00:13:38.909 still growing in Japan recently. How do analysts 00:13:38.909 --> 00:13:41.870 track all this? They use various models looking 00:13:41.870 --> 00:13:45.210 at correlations, regressions, time series analysis 00:13:45.210 --> 00:13:47.450 to try and understand the market dynamics and 00:13:47.450 --> 00:13:50.509 predict future sales. The market itself is broken 00:13:50.509 --> 00:13:52.789 down by dosage form two, catering to different 00:13:52.789 --> 00:13:56.059 patient needs. And the DPP4 class overall. Still 00:13:56.059 --> 00:13:58.940 important. Definitely. Despite newer options, 00:13:59.139 --> 00:14:02.159 DPP4 inhibitors like citagliptin are still considered 00:14:02.159 --> 00:14:04.419 a cornerstone treatment for type 2 diabetes by 00:14:04.419 --> 00:14:06.940 many, largely because they work well and have 00:14:06.940 --> 00:14:09.480 that low risk of hypoglycemia when used alone. 00:14:09.740 --> 00:14:13.000 Okay, last area. Cultural influence. How has 00:14:13.000 --> 00:14:15.419 a drug like sitagliptin shaped things beyond 00:14:15.419 --> 00:14:17.440 just the pharmacy shelf? Well, think about it. 00:14:17.440 --> 00:14:20.299 It's a widely used pill for a very common chronic 00:14:20.299 --> 00:14:23.539 disease. That alone gives it a huge impact on 00:14:23.539 --> 00:14:26.039 how type 2 diabetes is managed globally. The 00:14:26.039 --> 00:14:28.139 convenience factor. Yeah, the once -daily oral 00:14:28.139 --> 00:14:30.100 dose probably helps a lot with people actually 00:14:30.100 --> 00:14:32.779 taking their medication, regular adherence, we 00:14:32.779 --> 00:14:35.019 call it. And its success probably spurred more 00:14:35.019 --> 00:14:37.679 research. For sure. The focus on DPP4 as a target 00:14:37.679 --> 00:14:39.960 definitely encouraged more research and development 00:14:39.960 --> 00:14:42.559 in that whole class of drugs. and the safety 00:14:42.559 --> 00:14:45.409 discussions we had. pancreatitis, heart failure 00:14:45.409 --> 00:14:48.169 signals. Right. Those controversies have absolutely 00:14:48.169 --> 00:14:50.929 influenced treatment guidelines and how closely 00:14:50.929 --> 00:14:53.230 doctors monitor patients on these drugs now. 00:14:53.350 --> 00:14:55.110 You see information about it everywhere, too. 00:14:55.529 --> 00:14:58.269 Exactly. Websites like Medline Plus, the drug 00:14:58.269 --> 00:15:00.909 zone website. It reflects how many people use 00:15:00.909 --> 00:15:03.409 it and need reliable information. Even things 00:15:03.409 --> 00:15:05.750 like Merck's investor reports. Highlighting its 00:15:05.750 --> 00:15:08.309 financial importance. Yes. And showing the real 00:15:08.309 --> 00:15:10.929 world business impact of patent clips and competition. 00:15:11.490 --> 00:15:13.870 And finally, programs like patient assistance 00:15:13.870 --> 00:15:16.129 programs, trying to get the drug to people who 00:15:16.129 --> 00:15:18.990 can't afford it, that speaks to a broader societal 00:15:18.990 --> 00:15:22.029 role in healthcare access. Okay, so summing it 00:15:22.029 --> 00:15:26.029 all up. Citagliptin, a DbP4 inhibitor, really 00:15:26.029 --> 00:15:28.470 changed the game in type 2 diabetes management. 00:15:28.889 --> 00:15:31.590 It works by boosting in cretins, improving insulin 00:15:31.590 --> 00:15:34.370 release smartly, and lowering glucose production. 00:15:34.769 --> 00:15:36.889 Right. It became a massive commercial success, 00:15:36.909 --> 00:15:40.350 but now faces the inevitable decline due to patent 00:15:40.350 --> 00:15:43.009 expirations and competition. And its journey 00:15:43.009 --> 00:15:45.269 has been marked by important safety evaluations 00:15:45.269 --> 00:15:47.970 that continue to shape how it's used. Absolutely. 00:15:48.409 --> 00:15:51.580 This deep dive aimed to give you... our learner, 00:15:52.039 --> 00:15:54.200 that comprehensive picture based on the sources, 00:15:54.740 --> 00:15:57.559 a shortcut to getting up to speed on this significant 00:15:57.559 --> 00:16:00.159 medication. Hopefully we've achieved that, pulling 00:16:00.159 --> 00:16:02.539 together the science, the clinical use, the business 00:16:02.539 --> 00:16:04.960 side. And for a final thought, something for 00:16:04.960 --> 00:16:07.899 you to consider. We see all this ongoing research, 00:16:08.200 --> 00:16:10.100 newer diabetes drugs coming out with different 00:16:10.100 --> 00:16:13.240 mechanisms, some even showing direct heart benefits. 00:16:13.899 --> 00:16:16.600 So how do you think the role of DPP4 inhibitors 00:16:16.600 --> 00:16:19.340 like cytagliptin might shift or evolve in the 00:16:19.340 --> 00:16:21.960 future of diabetes care? Yeah, where will they 00:16:21.960 --> 00:16:23.840 fit in five, 10 years from now? It's a really 00:16:23.840 --> 00:16:25.600 interesting question to keep in mind. Definitely 00:16:25.600 --> 00:16:27.440 something to mull over. Thanks for joining us 00:16:27.440 --> 00:16:28.159 on this deep dive.