1 00:00:00,517 --> 00:00:01,494 Worldwide, cardiovascular 2 00:00:01,870 --> 00:00:04,678 disease affects the lives of hundreds of millions 3 00:00:04,735 --> 00:00:08,331 dedicated cardio nerds everywhere are working hard fight 4 00:00:08,331 --> 00:00:11,113 this global epidemic. These are their stories. 5 00:00:12,543 --> 00:00:15,564 Welcome, everyone. This is Rick Barr. Cardiology fellow 6 00:00:15,564 --> 00:00:17,649 at Johns Hopkins Hospital in c chair for 7 00:00:17,649 --> 00:00:20,925 the car intervention series. We are thrilled for 8 00:00:20,925 --> 00:00:23,163 today's episode, the first in a series focused 9 00:00:23,163 --> 00:00:23,902 on S 10 00:00:24,441 --> 00:00:24,921 inhibitors. 11 00:00:25,400 --> 00:00:27,168 Today we'll be focusing on the biology of 12 00:00:27,247 --> 00:00:27,747 S 13 00:00:28,521 --> 00:00:30,749 and it's inhibition. I am joined today by 14 00:00:30,749 --> 00:00:32,658 our c chair for this series Doctor. Gu 15 00:00:32,818 --> 00:00:35,125 Cow. Cardiology fellow at the B Women's. 16 00:00:35,539 --> 00:00:37,535 As well as director of the car Injured. 17 00:00:37,854 --> 00:00:39,211 Thank you so much for being here, Girl 18 00:00:39,371 --> 00:00:41,127 Great to Ceo. Thank you so much for 19 00:00:41,127 --> 00:00:44,081 that kind introduction. We're so excited for this 20 00:00:44,081 --> 00:00:46,013 episode and I'm really happy to introduce her 21 00:00:46,013 --> 00:00:48,250 fit lead for today, doctor S Humber, 22 00:00:49,129 --> 00:00:51,126 who is currently a cardiology fellow at the 23 00:00:51,206 --> 00:00:52,405 University at Miami, 24 00:00:52,739 --> 00:00:54,914 as well as cardio nerds academy faculty, 25 00:00:55,291 --> 00:00:57,206 so excited to have you here today ronald. 26 00:00:57,764 --> 00:00:59,700 Arlene, thank you so much for that kind 27 00:00:59,918 --> 00:01:01,832 introduction, and I'm so excited to learn more 28 00:01:01,832 --> 00:01:02,470 about this topic. 29 00:01:02,964 --> 00:01:04,642 It is my distinct pleasure to give our 30 00:01:04,642 --> 00:01:07,918 final welcome for today's expert discussion, doctor Catherine 31 00:01:08,078 --> 00:01:11,526 Tu. Doctor Tu is executive director for research 32 00:01:11,526 --> 00:01:12,720 at Providence healthcare, 33 00:01:13,197 --> 00:01:16,619 c principal investigator of the Institute of translational 34 00:01:16,619 --> 00:01:18,927 health sciences, and professor of Medicine at the 35 00:01:18,927 --> 00:01:19,962 university of Washington. 36 00:01:20,614 --> 00:01:23,250 Doctor Tu earned her medical degree and completed 37 00:01:23,250 --> 00:01:26,626 her residency and internal medicine at Northwestern University 38 00:01:26,765 --> 00:01:29,255 school of medicine. Followed by a fellowship in 39 00:01:29,255 --> 00:01:30,393 metabolism and endo 40 00:01:30,851 --> 00:01:31,909 at Washington university, 41 00:01:32,367 --> 00:01:34,841 in Saint. Louis, and a ne mythology fellowship 42 00:01:34,841 --> 00:01:38,131 training at University of Texas Health science center 43 00:01:38,131 --> 00:01:40,927 in San Antonio, Texas. Doctor Total has published 44 00:01:40,927 --> 00:01:42,146 over 250 45 00:01:42,285 --> 00:01:42,605 original... 46 00:01:43,335 --> 00:01:46,140 Contributions and served 2 terms as the associate 47 00:01:46,196 --> 00:01:48,899 director for the clinical journal of the American 48 00:01:49,137 --> 00:01:51,204 Society of Ne mythology and the American Journal 49 00:01:51,204 --> 00:01:54,411 of Kenya. Disease. Doctor Tu is also steering 50 00:01:54,411 --> 00:01:57,207 committee member for the cardio nerd supported zeus 51 00:01:57,207 --> 00:02:02,011 trial, testing inter 6 inhibitor, z v for 52 00:02:02,011 --> 00:02:03,149 secondary As 53 00:02:03,686 --> 00:02:06,159 prevention. Doctor Tu, thank you so much for 54 00:02:06,159 --> 00:02:08,073 your leadership and support of the cardio nerds 55 00:02:08,073 --> 00:02:10,321 clinical trials network and for joining us today. 56 00:02:10,800 --> 00:02:12,795 Well, thanks to all of you. It's really 57 00:02:12,795 --> 00:02:15,189 a pleasure to join you and to have 58 00:02:15,189 --> 00:02:17,996 a discussion about this super exciting topic it 59 00:02:17,996 --> 00:02:20,011 that really cuts across cardiology, 60 00:02:20,389 --> 00:02:20,889 ne 61 00:02:21,665 --> 00:02:22,404 and diabetes. 62 00:02:23,260 --> 00:02:24,776 Thank you so much, Doctor Tu. And with 63 00:02:24,855 --> 00:02:26,824 That let's just dive into today's discussion. 64 00:02:27,503 --> 00:02:29,418 So we'll start off with her case of 65 00:02:29,418 --> 00:02:32,451 mister Ronald Nap, a 58 year old man 66 00:02:32,451 --> 00:02:34,685 with a past medical history of obesity, 67 00:02:35,259 --> 00:02:37,970 type 2 diabetes mel colitis and heart failure 68 00:02:37,970 --> 00:02:40,761 with an ef of 32 percent, who comes 69 00:02:40,761 --> 00:02:43,095 into the clinic after a recent heart failure 70 00:02:43,153 --> 00:02:43,653 ex. 71 00:02:44,443 --> 00:02:47,172 His current medications are metformin, Carved, 72 00:02:47,786 --> 00:02:50,094 sac Val sa and act. 73 00:02:50,651 --> 00:02:53,357 His relevant laboratory values are a hemoglobin a 74 00:02:53,357 --> 00:02:54,726 a1c of 7.8, 75 00:02:55,204 --> 00:02:56,978 Cr of 1.3 76 00:02:57,036 --> 00:02:58,390 and G 48. 77 00:02:59,027 --> 00:03:01,576 Doctor Total, how would you approach optimizing mister 78 00:03:01,736 --> 00:03:03,032 Ne medication regimen 79 00:03:03,344 --> 00:03:05,818 And what is the evidence supporting indications for 80 00:03:05,818 --> 00:03:08,451 this patient to start an S 2 inhibitor 81 00:03:08,451 --> 00:03:11,735 at this visit? Well, clearly, s Gl 2 82 00:03:11,735 --> 00:03:13,485 inhibitors are the fourth pillar, 83 00:03:13,962 --> 00:03:16,507 not only for heart failure, but for chronic 84 00:03:16,507 --> 00:03:17,303 kidney disease. 85 00:03:18,194 --> 00:03:18,912 He has both. 86 00:03:19,551 --> 00:03:20,988 1 of the things I really like to 87 00:03:20,988 --> 00:03:22,925 know is what his level of Albumin 88 00:03:23,382 --> 00:03:25,958 is as the urine albumin to cr 89 00:03:26,416 --> 00:03:26,916 ratio 90 00:03:27,467 --> 00:03:30,095 because we think about risk based strategies in 91 00:03:30,095 --> 00:03:31,949 addition to conventional cardiovascular 92 00:03:32,324 --> 00:03:33,041 risk factors. 93 00:03:33,758 --> 00:03:36,322 We also now recommend looking at E r 94 00:03:36,322 --> 00:03:39,114 albumin, for example, in the new prevent equations. 95 00:03:39,831 --> 00:03:41,586 But that said, this is enough for me 96 00:03:41,586 --> 00:03:43,102 to start an ST2 97 00:03:43,102 --> 00:03:45,255 inhibitor on the basis of heart failure alone. 98 00:03:45,908 --> 00:03:48,620 Also, even taking into account the Ck k 99 00:03:48,620 --> 00:03:51,412 angle, we know for imp kidney that even 100 00:03:51,412 --> 00:03:53,985 in patients without an increase in albumin men 101 00:03:54,044 --> 00:03:57,026 if G far is low, There's broad benefit 102 00:03:57,479 --> 00:03:58,534 across cardiovascular 103 00:03:59,384 --> 00:04:02,638 and kidney outcomes. So clearly, he needs support 104 00:04:02,638 --> 00:04:03,987 pillar attitudes regimen, 105 00:04:04,558 --> 00:04:06,547 His a 1 a1c is a little higher 106 00:04:06,547 --> 00:04:08,854 that I'd like to see it. Ideally, we'd 107 00:04:08,854 --> 00:04:10,445 like to see the a 1 a1c less 108 00:04:10,445 --> 00:04:13,191 than 7 to reduce risk of diabetes 109 00:04:13,887 --> 00:04:16,599 complications, heart and kidney, but also from the 110 00:04:16,599 --> 00:04:18,534 standpoint of thinking more holistically 111 00:04:18,992 --> 00:04:20,986 about retinopathy and neuropathy, 112 00:04:21,559 --> 00:04:22,059 The 113 00:04:22,435 --> 00:04:25,086 S 2 inhibitor will have only a modest 114 00:04:25,303 --> 00:04:26,339 glucose lowering effect, 115 00:04:27,136 --> 00:04:29,924 particularly when G r drops below 45, and 116 00:04:29,924 --> 00:04:32,173 he's close to that. We see an att 117 00:04:32,173 --> 00:04:33,152 continuation of the gl 118 00:04:33,691 --> 00:04:34,431 efficacy, although 119 00:04:34,810 --> 00:04:37,227 efficacy for heart failure and Ck 120 00:04:37,686 --> 00:04:39,932 progression or preserve, But then said, I think 121 00:04:39,932 --> 00:04:42,158 that it would be prudent to start the 122 00:04:42,238 --> 00:04:45,838 S 2 inhibitor and then reassess him relatively 123 00:04:46,053 --> 00:04:46,371 soon. 124 00:04:46,944 --> 00:04:49,019 Again, from a clinical standpoint, from a heart 125 00:04:49,019 --> 00:04:52,372 failure standpoint, but also reassess risk factors so 126 00:04:52,372 --> 00:04:54,368 for example, if the 1 a1c stop coming 127 00:04:54,368 --> 00:04:57,019 down, we may add another agent, diaz persistent 128 00:04:57,019 --> 00:04:59,660 elevated albumin, we might do something else too. 129 00:05:00,139 --> 00:05:02,060 Thank you so much for outlining your logic 130 00:05:02,060 --> 00:05:02,860 there, doctor Tu. 131 00:05:03,514 --> 00:05:05,675 Now, how about we dive into the biology 132 00:05:05,675 --> 00:05:08,875 and mechanisms of S inhibitors, including both their 133 00:05:08,875 --> 00:05:12,327 direct and indirect effects? We know ST2 134 00:05:12,327 --> 00:05:14,884 inhibitors were initially developed as anti diabetic agents. 135 00:05:15,283 --> 00:05:17,121 So to get us started, Doctor Tu, can 136 00:05:17,121 --> 00:05:18,893 you please share with us how s Lt 137 00:05:18,893 --> 00:05:21,924 2 inhibitors improve ac control. To be honest 138 00:05:21,924 --> 00:05:24,636 with you, this goes back many years. And, 139 00:05:25,035 --> 00:05:27,268 in fact, in 19 87 along with doctor 140 00:05:27,348 --> 00:05:30,148 D, we gave morrison to diabetic grass. 141 00:05:30,784 --> 00:05:34,360 And initially, the goal was to reduce glucose 142 00:05:34,360 --> 00:05:35,552 without raising insulin. 143 00:05:36,203 --> 00:05:39,221 And we were doing physiology studies, so we're 144 00:05:39,221 --> 00:05:42,796 trying to prove the glucose toxicity theory that 145 00:05:42,796 --> 00:05:45,995 you could lower glucose without raising insulin and 146 00:05:45,995 --> 00:05:46,734 show pancreatic 147 00:05:47,350 --> 00:05:49,583 preservation. But that said, Ralph and I were 148 00:05:49,583 --> 00:05:50,540 also ne neurologists. 149 00:05:51,019 --> 00:05:52,534 And we had a lot of discussion about 150 00:05:52,534 --> 00:05:55,420 what would happen with regard kidney hem or 151 00:05:55,420 --> 00:05:56,478 gl hem 152 00:05:57,414 --> 00:05:59,807 because these agents cause loss of glucose in 153 00:05:59,807 --> 00:06:00,285 the urine. 154 00:06:00,923 --> 00:06:03,635 And this ob not only loss of glucose, 155 00:06:03,715 --> 00:06:04,924 but sodium chloride. 156 00:06:05,481 --> 00:06:08,662 When these agents are given, re reabsorption of 157 00:06:08,662 --> 00:06:10,572 glucose is blocked to the proxima tub, 158 00:06:11,064 --> 00:06:14,740 and downstream then both glucose and sodium chloride 159 00:06:14,796 --> 00:06:17,813 are increased. This has profound effects on kidney 160 00:06:17,813 --> 00:06:18,631 hem thermodynamics. 161 00:06:19,178 --> 00:06:21,586 And it turns out that those changes 162 00:06:21,961 --> 00:06:25,539 actually reduce something we call hyper filtration. Now 163 00:06:25,539 --> 00:06:27,383 why am I talking to cardio nerds about 164 00:06:27,383 --> 00:06:28,896 this. Well it turns out when we correct 165 00:06:28,896 --> 00:06:29,555 gl molecular 166 00:06:30,090 --> 00:06:33,138 filtration. There's systemic effects. That are very favorable 167 00:06:33,434 --> 00:06:35,915 for the heart. There is a reduction in 168 00:06:35,915 --> 00:06:38,480 blood pressure. There's reductions said that synthetic neural 169 00:06:38,535 --> 00:06:42,347 activity. There's a glucose uric effect that improves 170 00:06:42,347 --> 00:06:42,847 diarrhea 171 00:06:43,553 --> 00:06:46,519 And then systemically, there an increase in a 172 00:06:46,735 --> 00:06:49,678 wheaton, which raises red blood cells at oxygen 173 00:06:49,678 --> 00:06:52,797 carrying capacity. So this culminate in a number 174 00:06:52,797 --> 00:06:56,959 of favorable effects on cardiac function. Also glucose 175 00:06:57,255 --> 00:06:58,312 induces a mild 176 00:06:58,703 --> 00:07:01,889 ketosis by increasing free fatty acid metabolism, and 177 00:07:01,889 --> 00:07:02,867 in a mild 178 00:07:03,244 --> 00:07:06,213 degree, for example, increase of data hydro 179 00:07:06,749 --> 00:07:09,308 is a preferred my cardio fuel. So it 180 00:07:09,308 --> 00:07:12,723 turns out that very interestingly, these changes at 181 00:07:12,723 --> 00:07:15,844 the level of the gl and real tub 182 00:07:16,234 --> 00:07:18,567 have profound effects on the systemic 183 00:07:18,944 --> 00:07:21,256 circulation that make heart function better. And I 184 00:07:21,256 --> 00:07:23,430 think this is something that's really been under 185 00:07:23,567 --> 00:07:25,993 underappreciated as this If you will delicate dance 186 00:07:26,050 --> 00:07:28,755 between heart function and kidney function, so bottom 187 00:07:28,755 --> 00:07:31,619 line is lower blood pressure less sympathetic neuro 188 00:07:31,619 --> 00:07:33,131 activity, lower plasma volume, 189 00:07:33,862 --> 00:07:36,727 increase for poly red cell mass and oxygen 190 00:07:36,727 --> 00:07:38,978 carrying capacity, lower beta hydro, 191 00:07:39,911 --> 00:07:41,821 all of which in the setting of heart 192 00:07:41,821 --> 00:07:45,187 failure improves cardiac fo. Doctor Total, that was 193 00:07:45,187 --> 00:07:47,125 so fantastic. You know, We have this 194 00:07:47,584 --> 00:07:49,662 kind of message group that while we talk 195 00:07:49,662 --> 00:07:51,580 about the episode and and there's so many 196 00:07:51,580 --> 00:07:53,514 pearls that I've gotta go back and listen 197 00:07:53,514 --> 00:07:55,754 to and and that we've been pulling out 198 00:07:55,754 --> 00:07:55,995 here. 199 00:07:56,555 --> 00:07:58,235 But 1 thing that's really obvious is I 200 00:07:58,235 --> 00:07:59,375 think a lot of the time 201 00:07:59,769 --> 00:08:02,566 people think of probably incorrect definitely incorrectly. 202 00:08:03,046 --> 00:08:05,922 Of ne neurologists and cardiologist is is almost 203 00:08:05,922 --> 00:08:08,574 antagonist. Is almost on other sides of For 204 00:08:08,574 --> 00:08:11,368 example, the diuretic spectrum, but it's so cool 205 00:08:11,368 --> 00:08:12,725 with these ST2 206 00:08:12,725 --> 00:08:15,280 drugs that it's really all coming together to 207 00:08:15,280 --> 00:08:17,276 move patient care forward, and that's really, really 208 00:08:17,276 --> 00:08:17,435 cool. 209 00:08:18,167 --> 00:08:20,547 So while these agents were first primarily used 210 00:08:20,547 --> 00:08:23,561 for diabetes, subsequent cardiovascular outcome trial, some of 211 00:08:23,561 --> 00:08:26,598 which we've already discussed have shown improved outcomes 212 00:08:26,598 --> 00:08:29,250 in patients with type 2 diabetes, 213 00:08:29,626 --> 00:08:32,017 and as well as independent of diabetes status. 214 00:08:32,828 --> 00:08:34,260 Would you mind discussing a little bit the 215 00:08:34,260 --> 00:08:36,964 background for understanding the mechanism of these medication 216 00:08:36,964 --> 00:08:37,442 classes? 217 00:08:38,078 --> 00:08:41,022 And specifically, how do they exert cardio protective 218 00:08:41,022 --> 00:08:42,890 and renal protective benefits 219 00:08:43,505 --> 00:08:45,258 outside of their effects of gl control. And 220 00:08:45,337 --> 00:08:46,532 I know some of this you discussed a 221 00:08:46,532 --> 00:08:48,523 little bit, but is there anything else that 222 00:08:48,523 --> 00:08:50,276 you think will be worth hearing viral centers? 223 00:08:50,769 --> 00:08:52,863 Well, what we're now recognizing 224 00:08:53,719 --> 00:08:56,110 is there are some off target effects of 225 00:08:56,110 --> 00:08:58,843 the S 2 inhibitors, but back to biology 226 00:08:59,061 --> 00:09:00,990 again that's what you invited me to talk 227 00:09:00,990 --> 00:09:03,384 about. 1 of the really interesting things. This 228 00:09:03,384 --> 00:09:06,495 is the S 2 receptor is only found. 229 00:09:06,989 --> 00:09:10,100 In the proxima convoluted tub. So the off 230 00:09:10,100 --> 00:09:12,753 target effects are not receptor mediated. 231 00:09:13,609 --> 00:09:15,763 So all of the effects I just described 232 00:09:15,763 --> 00:09:17,634 to you that affect kidney hem 233 00:09:18,335 --> 00:09:21,215 that have systemic effects to improve heart function. 234 00:09:21,934 --> 00:09:24,908 Are mediated by the S 2 receptor in 235 00:09:24,908 --> 00:09:27,053 the proxima tub. So again, back to what 236 00:09:27,053 --> 00:09:29,199 you said, I think that what we're seeing 237 00:09:29,199 --> 00:09:31,742 is synergy non antagonist in terms of both 238 00:09:31,742 --> 00:09:33,093 kidney and heart protection. 239 00:09:33,823 --> 00:09:36,044 Now with regard to the off target effects, 240 00:09:36,600 --> 00:09:39,297 what we have learned is the S 2 241 00:09:39,297 --> 00:09:39,797 inhibitors 242 00:09:40,170 --> 00:09:41,598 enter a number of cells. 243 00:09:42,169 --> 00:09:45,297 They enter cells by non receptor mediated mechanisms 244 00:09:45,753 --> 00:09:48,005 and the cells, for example, in cardiac 245 00:09:49,018 --> 00:09:50,793 with S 2 inhibitors 246 00:09:51,344 --> 00:09:52,004 intra cardiac, 247 00:09:53,022 --> 00:09:55,738 they actually block glucose transport into the cell, 248 00:09:55,978 --> 00:09:58,375 like blocking glut 1 and 4 receptors. 249 00:09:59,029 --> 00:10:01,604 They in addition reduce a signal 250 00:10:02,221 --> 00:10:05,753 pathway called M torque, which not only promotes 251 00:10:06,211 --> 00:10:08,483 inflammation but also promotes gl. 252 00:10:09,102 --> 00:10:11,200 So long story short for cardiologist 253 00:10:11,579 --> 00:10:13,657 is we see a state of reduced le 254 00:10:13,657 --> 00:10:15,975 glucose intake and reduced gl, which is a 255 00:10:15,975 --> 00:10:18,695 relative state of cell starvation, but that's actually 256 00:10:18,695 --> 00:10:20,943 cardio protected in a sick cardiac. 257 00:10:21,874 --> 00:10:24,832 Also, when we block mt torque with the 258 00:10:24,912 --> 00:10:25,948 S22 259 00:10:25,948 --> 00:10:29,535 inhibitor directly. There's a reduction in expression of 260 00:10:29,535 --> 00:10:32,267 inflammatory meters, which is also another mechanism 261 00:10:32,817 --> 00:10:35,379 of progression of heart failure and cardiomyopathy. 262 00:10:35,990 --> 00:10:37,894 And then finally, at the level of the 263 00:10:37,894 --> 00:10:40,035 kidney these changes are happening a number of 264 00:10:40,035 --> 00:10:43,071 kidney cells. Too, so the kidney protection is 265 00:10:43,071 --> 00:10:44,366 in addition to hem, 266 00:10:44,741 --> 00:10:47,310 these direct effects that are intra cellular. 267 00:10:47,859 --> 00:10:50,986 And 1, they'll emphasize again that's really important 268 00:10:51,202 --> 00:10:52,817 is the increase in 269 00:10:53,351 --> 00:10:56,231 hemoglobin is not a delusional effect. It's a 270 00:10:56,231 --> 00:10:59,014 real increase in red cell mass, and this 271 00:10:59,014 --> 00:11:01,716 is because in the kidney fiber, which are 272 00:11:01,716 --> 00:11:03,068 not the tubular cells. 273 00:11:03,799 --> 00:11:05,017 This is where a 274 00:11:05,474 --> 00:11:07,489 magnet. It turns out in those fiber, 275 00:11:08,106 --> 00:11:11,615 S 2 inhibitors actually have a s effect 276 00:11:11,615 --> 00:11:14,260 on a signal called cert 1. And insert 277 00:11:14,260 --> 00:11:16,510 1 increases expression of. 278 00:11:17,600 --> 00:11:20,463 So I think it's important to recognize that 279 00:11:20,463 --> 00:11:22,809 the hem of that's are probably 280 00:11:23,268 --> 00:11:23,768 predominant, 281 00:11:24,546 --> 00:11:26,863 but there are other off target facts in 282 00:11:26,863 --> 00:11:29,100 multiple cell types of the kidney and the 283 00:11:29,100 --> 00:11:32,305 heart that so far have been protective, that 284 00:11:32,305 --> 00:11:34,218 if there's not been a a sign effect 285 00:11:34,218 --> 00:11:36,052 if you will an off target effect that's 286 00:11:36,052 --> 00:11:37,646 been found to be adverse. 287 00:11:38,219 --> 00:11:40,773 At the cellular level. There are some side 288 00:11:40,773 --> 00:11:42,688 effects that we'll talk about, but they're not 289 00:11:42,688 --> 00:11:44,364 related to these actions. 290 00:11:45,082 --> 00:11:45,880 And finally, 291 00:11:46,374 --> 00:11:49,403 The other reason that these are important, S 292 00:11:49,403 --> 00:11:51,737 2 inhibitors have really been the biggest gift 293 00:11:51,955 --> 00:11:54,347 today for both heart failure and chronic kidney 294 00:11:54,347 --> 00:11:54,586 disease. 295 00:11:55,158 --> 00:11:57,386 And when we understand more about how they 296 00:11:57,386 --> 00:11:59,694 work, we could even think about better drug 297 00:11:59,694 --> 00:12:02,971 targets, for example, now knowing the effects of 298 00:12:03,050 --> 00:12:05,990 S 2 inhibitors to block m torque. While 299 00:12:05,990 --> 00:12:07,205 this gives us biological 300 00:12:07,578 --> 00:12:09,405 rationale to maybe just go straight for an 301 00:12:09,405 --> 00:12:12,525 m torque inhibitor 4 subsets of patients who 302 00:12:12,525 --> 00:12:15,077 may progress despite the fork pillars up there. 303 00:12:15,715 --> 00:12:17,709 Doctor Total, thanks for truly taking us back 304 00:12:17,709 --> 00:12:19,863 to the core biology from the level of 305 00:12:19,863 --> 00:12:23,003 the She to chapter in the proxima tub 306 00:12:23,058 --> 00:12:25,123 to effects really related to gl to the 307 00:12:25,123 --> 00:12:25,917 mt pathway. 308 00:12:26,393 --> 00:12:29,116 It's really helpful to understand the potential mechanisms 309 00:12:29,330 --> 00:12:32,691 through how S 2 inhibitors exert their cardio 310 00:12:32,691 --> 00:12:35,082 renal protection. And so far in this discussion, 311 00:12:35,242 --> 00:12:37,554 we've been really focusing in on S 2 312 00:12:37,554 --> 00:12:38,532 inhibitors particularly 313 00:12:39,004 --> 00:12:40,832 but we do know that there's agents studied 314 00:12:40,832 --> 00:12:43,558 in clinical trials such as so 315 00:12:44,330 --> 00:12:46,397 that is a dual ST1 316 00:12:46,397 --> 00:12:47,987 and S 2 inhibitor. 317 00:12:48,559 --> 00:12:50,559 And we had recent data from the Solo 318 00:12:50,639 --> 00:12:53,940 W f and score trial that showed benefit 319 00:12:54,000 --> 00:12:54,740 with so 320 00:12:55,120 --> 00:12:55,860 for cardiovascular 321 00:12:56,399 --> 00:12:56,559 outcomes. 322 00:12:57,213 --> 00:12:58,489 Can you tell us a little bit more 323 00:12:58,489 --> 00:13:01,061 about the biology of S 1 transporter? 324 00:13:01,597 --> 00:13:04,647 Where are these located and does S 1 325 00:13:04,879 --> 00:13:07,117 and also play a role in potential cardio 326 00:13:07,117 --> 00:13:07,916 protective benefits? 327 00:13:08,555 --> 00:13:11,453 Yes. That's a great question. The the rationale 328 00:13:11,592 --> 00:13:13,830 for the S 1 inhibition, and by the 329 00:13:13,830 --> 00:13:17,101 way, flo original agent that we used in 330 00:13:17,101 --> 00:13:20,592 the route model was a combined S12 331 00:13:20,592 --> 00:13:20,989 inhibitor. 332 00:13:21,799 --> 00:13:22,299 And 333 00:13:22,837 --> 00:13:25,392 the reason that we look for S 2 334 00:13:25,392 --> 00:13:26,850 first is mainly 335 00:13:27,228 --> 00:13:28,904 because of the side of that profile. I'll 336 00:13:28,904 --> 00:13:31,633 come back to the rationale work returning a 337 00:13:31,633 --> 00:13:33,380 combined ST12 338 00:13:33,380 --> 00:13:34,595 inhibition, But I just wanna 339 00:13:35,287 --> 00:13:36,264 emphasize why 340 00:13:36,638 --> 00:13:37,829 we didn't do that first. 341 00:13:38,718 --> 00:13:42,530 Is that S 1 receptors are found in 342 00:13:42,530 --> 00:13:45,651 places of science kidney, particularly that gut 343 00:13:46,025 --> 00:13:46,422 epithelium. 344 00:13:47,072 --> 00:13:49,690 And 1 of the major limiting side effects 345 00:13:49,690 --> 00:13:52,070 of using the agents is diarrhea, which can 346 00:13:52,070 --> 00:13:53,522 be quite disabling 347 00:13:54,070 --> 00:13:57,450 And now, again, originally, they were used 348 00:13:57,909 --> 00:13:59,450 exclusively in diabetes 349 00:14:00,070 --> 00:14:03,285 populations and in particular people who had kidney 350 00:14:03,285 --> 00:14:06,024 disease or heart disease often have gas 351 00:14:06,565 --> 00:14:09,304 and and autonomic neuropathy the... And the diarrhea 352 00:14:09,699 --> 00:14:12,670 that resulted with adding the S 1 was 353 00:14:12,887 --> 00:14:16,154 quite challenging for many patients. But be that 354 00:14:16,154 --> 00:14:19,445 as it may, there was still rationale for 355 00:14:19,445 --> 00:14:21,625 considering adding S 1 356 00:14:22,085 --> 00:14:24,425 because there are s 1 receptors 357 00:14:24,738 --> 00:14:27,467 in the kidney pro tub, not the pro 358 00:14:27,524 --> 00:14:30,389 convoluted tub which is the most proxima part, 359 00:14:30,548 --> 00:14:31,503 the pro tub. 360 00:14:32,060 --> 00:14:33,038 So downstream 361 00:14:33,413 --> 00:14:33,913 from 362 00:14:34,304 --> 00:14:35,284 that convoluted 363 00:14:35,823 --> 00:14:37,501 part of the tub bill so the straight 364 00:14:37,501 --> 00:14:40,138 part of the proxima tub their S 1 365 00:14:40,138 --> 00:14:43,826 receptors. The rationale again originally came for glucose 366 00:14:43,826 --> 00:14:45,837 lowering because about 90 367 00:14:46,848 --> 00:14:50,188 percent of the glucose re uptake occurs in 368 00:14:50,188 --> 00:14:54,182 the proxima con tub by the ST2 369 00:14:54,182 --> 00:14:58,251 receptors, But close to 10 percent is mediated 370 00:14:58,251 --> 00:15:00,659 by the ST1. So the idea was you 371 00:15:00,659 --> 00:15:02,812 know, maybe you can get additional glucose lowering 372 00:15:02,812 --> 00:15:06,003 by blocking both receptors and hopefully people would 373 00:15:06,003 --> 00:15:08,156 be able to tolerate the Gi side effects. 374 00:15:08,555 --> 00:15:10,150 So that was the original rationale. 375 00:15:11,124 --> 00:15:14,160 Again, back to the first question about development 376 00:15:14,160 --> 00:15:15,918 of these agents for glucose. 377 00:15:16,397 --> 00:15:18,969 But the idea that was as well, you 378 00:15:18,969 --> 00:15:21,622 know, if these agents have greater gl 379 00:15:22,079 --> 00:15:23,457 efficacy it's because there's greater 380 00:15:24,073 --> 00:15:26,727 and back again, the first question. The reason 381 00:15:28,141 --> 00:15:28,641 is 382 00:15:28,954 --> 00:15:31,051 important from the standpoint of heart and kidney 383 00:15:31,269 --> 00:15:33,206 protection is could we get more complete 384 00:15:33,584 --> 00:15:36,937 restoration or normalization of or hem that then 385 00:15:36,937 --> 00:15:38,076 in turn would translate 386 00:15:38,548 --> 00:15:40,084 into even better 387 00:15:40,539 --> 00:15:43,668 systemic of effects that flow from improving gl 388 00:15:43,725 --> 00:15:44,225 hem. 389 00:15:44,999 --> 00:15:47,879 So, yes, in those 2 trials, There were 390 00:15:47,879 --> 00:15:48,934 favorable cardiovascular 391 00:15:49,385 --> 00:15:51,844 benefits. The question though is that they haven't 392 00:15:51,844 --> 00:15:53,826 really even studied head to head versus an 393 00:15:53,905 --> 00:15:56,620 S 2. And it, you know, between trials, 394 00:15:56,779 --> 00:15:59,403 you really can't make direct comparisons. So I 395 00:15:59,403 --> 00:16:01,628 think the real question is if there is 396 00:16:01,628 --> 00:16:02,741 a gain from it. 397 00:16:03,474 --> 00:16:05,552 Is it gonna be worth the side effect, 398 00:16:05,871 --> 00:16:08,349 particularly the management, the Gi side effects? 399 00:16:09,468 --> 00:16:11,706 Doctor Tu, thank you so much for breaking 400 00:16:11,706 --> 00:16:14,584 down, not just the complex biological mechanisms of 401 00:16:14,584 --> 00:16:17,995 these drugs, but also providing some historical context 402 00:16:17,995 --> 00:16:19,764 to the decisions to 403 00:16:20,153 --> 00:16:22,380 study certain drugs prior her to others. But 404 00:16:22,380 --> 00:16:24,608 as you've alluded to a few times, as 405 00:16:24,608 --> 00:16:26,995 clinicians whenever we prescribe any class of medications, 406 00:16:27,154 --> 00:16:29,159 we really have to be very thoughtful of 407 00:16:29,159 --> 00:16:31,157 the potential side effects and what to counsel 408 00:16:31,157 --> 00:16:33,714 patients regarding. Doctor Tu, would you please be 409 00:16:33,714 --> 00:16:35,073 able to tell us a little bit more 410 00:16:35,073 --> 00:16:36,931 about the common side effects of the S 411 00:16:36,990 --> 00:16:39,876 2 inhibitors and the dual ST1 412 00:16:39,876 --> 00:16:42,346 and 2 inhibitors and the mechanisms behind them? 413 00:16:42,585 --> 00:16:44,657 And to that same point, are there certain 414 00:16:44,657 --> 00:16:46,808 patient populations that are at higher risk for 415 00:16:46,808 --> 00:16:47,446 these side effects? 416 00:16:48,416 --> 00:16:50,645 Sure. And I guess just because mary it 417 00:16:50,645 --> 00:16:52,794 started with the ST1. 418 00:16:53,192 --> 00:16:55,522 The mechanism behind the diarrhea 419 00:16:55,898 --> 00:16:57,512 is because they're 420 00:16:57,902 --> 00:17:00,391 actually is less glucose reabsorption 421 00:17:00,766 --> 00:17:03,573 in the gut. So basically, it's an os 422 00:17:04,107 --> 00:17:06,278 type of diarrhea, like the os 423 00:17:06,589 --> 00:17:07,089 dia. 424 00:17:07,390 --> 00:17:08,930 So that's the main 425 00:17:09,390 --> 00:17:11,650 additional sign effect of the S 426 00:17:12,029 --> 00:17:14,990 1 car. With regard to S 2, there's 427 00:17:14,990 --> 00:17:17,725 are some important side effects and almost all 428 00:17:17,725 --> 00:17:19,025 of them relate to the. 429 00:17:20,125 --> 00:17:22,785 So most common what we see are gen 430 00:17:22,924 --> 00:17:25,890 urinary infection because having glucose in the urine 431 00:17:25,890 --> 00:17:27,346 is fodder for 432 00:17:28,199 --> 00:17:30,907 bacteria fungus. And in fact, what most common 433 00:17:30,907 --> 00:17:33,468 or gen psychotic such and they can occur 434 00:17:33,468 --> 00:17:35,796 in men as well as women, and women 435 00:17:35,852 --> 00:17:38,156 about 4 to 5 percent, but in men, 436 00:17:38,236 --> 00:17:40,302 it's about half that that's still 2 to 437 00:17:40,302 --> 00:17:41,097 3 percent. 438 00:17:41,749 --> 00:17:44,147 So all patients need to be counsel about 439 00:17:44,147 --> 00:17:47,104 h genetic measures and in studies where patients 440 00:17:47,104 --> 00:17:48,323 have received counseling 441 00:17:48,702 --> 00:17:51,154 about daily bathing and clean close those risks 442 00:17:51,354 --> 00:17:52,713 can be reduced and have. 443 00:17:53,352 --> 00:17:55,190 Most of the time they're mild and we 444 00:17:55,190 --> 00:17:57,108 can treat through them and keep them on 445 00:17:57,108 --> 00:17:59,745 life saving therapy without having to stop them. 446 00:18:00,319 --> 00:18:02,874 But in some cases it may be severe 447 00:18:02,874 --> 00:18:05,269 and that can be a limitation to use 448 00:18:05,269 --> 00:18:06,227 of these agents, 449 00:18:07,025 --> 00:18:09,361 especially in people who may be I compromised 450 00:18:09,914 --> 00:18:10,314 example. 451 00:18:11,033 --> 00:18:13,990 The other 1 can be volume depletion. Now 452 00:18:13,990 --> 00:18:16,807 on our fields where we're dealing with volume 453 00:18:17,106 --> 00:18:19,678 overload and more commonly than that, the raises 454 00:18:19,678 --> 00:18:22,235 is often a welcome side effect, but there 455 00:18:22,235 --> 00:18:24,393 are some patients who do have tenuous volume 456 00:18:24,393 --> 00:18:25,991 status and then those people we have to 457 00:18:25,991 --> 00:18:26,630 be cautious. 458 00:18:27,284 --> 00:18:28,560 About volume depletion, 459 00:18:29,438 --> 00:18:31,613 and might even consider proactively 460 00:18:32,150 --> 00:18:33,746 reducing a diuretic dose. 461 00:18:34,476 --> 00:18:36,855 Ahead of starting an S 2 inhibitor, and 462 00:18:37,013 --> 00:18:39,075 I think this brings up another issue about 463 00:18:39,154 --> 00:18:41,453 S twos is as opposed to say statins. 464 00:18:42,023 --> 00:18:44,963 These aren't really fire forget therapies. People do 465 00:18:44,963 --> 00:18:47,109 need to be managed on those. And after 466 00:18:47,109 --> 00:18:50,069 starting an S 2 inhibitor At least at 467 00:18:50,069 --> 00:18:52,306 our practice, we see people back within 2 468 00:18:52,306 --> 00:18:55,183 to 4 weeks to recheck labs, E our 469 00:18:55,183 --> 00:18:56,781 of potassium, in particular, 470 00:18:57,181 --> 00:18:58,000 but also, 471 00:18:58,634 --> 00:18:59,611 a good clinical 472 00:19:00,066 --> 00:19:02,613 evaluation for volume status and blood pressure. And 473 00:19:02,613 --> 00:19:04,545 that brings up the other things. Some people 474 00:19:04,602 --> 00:19:07,330 because of the diuretic effect can become hypo. 475 00:19:08,199 --> 00:19:10,109 And this brings up this issue with the 476 00:19:10,189 --> 00:19:13,852 G deck. So up to 30 percent decline 477 00:19:13,852 --> 00:19:16,263 in G is a dip that we attribute 478 00:19:16,654 --> 00:19:18,805 to reducing gl hyper filtration, 479 00:19:19,522 --> 00:19:22,072 har back to the physiology that we talked 480 00:19:22,072 --> 00:19:24,159 about, in which case, it's a good thing. 481 00:19:24,398 --> 00:19:26,015 It's actually a read for therapeutic 482 00:19:26,393 --> 00:19:29,025 responsiveness fitness, so like in da Ck arcadia 483 00:19:29,025 --> 00:19:29,663 and credence, 484 00:19:30,141 --> 00:19:33,353 G dips up to 30 percent actually predicted 485 00:19:33,411 --> 00:19:33,911 benefit 486 00:19:34,304 --> 00:19:35,442 on kidney and cardiovascular 487 00:19:36,060 --> 00:19:36,879 outcomes. However, 488 00:19:37,576 --> 00:19:39,971 if there's more than a 30 percent decline, 489 00:19:40,290 --> 00:19:42,445 then we need to think about other issues. 490 00:19:42,939 --> 00:19:47,086 Usually, it's volume depletion or hypotension, and most 491 00:19:47,086 --> 00:19:48,224 people will 492 00:19:48,681 --> 00:19:51,553 improve by simply backing off diuretics or other 493 00:19:51,553 --> 00:19:52,053 anti. 494 00:19:53,559 --> 00:19:55,787 Then the other big side effect that gets 495 00:19:55,787 --> 00:19:57,639 a lot of place the so called 496 00:19:58,173 --> 00:19:58,673 keto. 497 00:19:59,859 --> 00:20:02,808 This occurs most commonly in people with type 498 00:20:02,808 --> 00:20:05,598 2 diabetes, long standing insulin users. 499 00:20:06,315 --> 00:20:06,975 In those 500 00:20:07,352 --> 00:20:08,742 individuals, it's the gl, 501 00:20:09,116 --> 00:20:12,293 the resulting increase in free fatty acid oxidation 502 00:20:12,293 --> 00:20:14,120 that leads to mild ketosis. 503 00:20:14,596 --> 00:20:15,946 But in those individuals, 504 00:20:16,836 --> 00:20:19,622 especially with stress of acute illness, whether it's 505 00:20:19,622 --> 00:20:23,123 a viral infection or something else can tip 506 00:20:23,123 --> 00:20:24,499 them into a keto 507 00:20:25,352 --> 00:20:25,805 without 508 00:20:26,243 --> 00:20:26,982 severe hyper. 509 00:20:27,998 --> 00:20:30,891 And here the best defense against keto 510 00:20:31,428 --> 00:20:33,741 is maintaining some insulin board. 511 00:20:34,459 --> 00:20:37,585 So even if they have a lowering of 512 00:20:37,585 --> 00:20:39,501 glucose if you have to back off it's 513 00:20:39,501 --> 00:20:41,896 something you could actually reduce the ST2 514 00:20:41,896 --> 00:20:42,135 inhibitor. 515 00:20:42,774 --> 00:20:44,131 Because the ST2 516 00:20:44,131 --> 00:20:46,299 inhibitor benefit on heart and kidney, 517 00:20:47,176 --> 00:20:50,366 protection is not dose dependent, but glucose lowering 518 00:20:50,366 --> 00:20:52,860 is. So there we recommend keep a little 519 00:20:52,998 --> 00:20:53,556 insulin on, 520 00:20:54,129 --> 00:20:56,047 and reduce the ST2, 521 00:20:56,207 --> 00:20:58,525 but keep the S 2 on board. It 522 00:20:58,525 --> 00:21:01,822 is very rare to seek keto acidosis in 523 00:21:01,961 --> 00:21:02,781 non diabetic 524 00:21:03,160 --> 00:21:06,116 individuals But again, even in people without diabetes, 525 00:21:06,593 --> 00:21:09,452 starvation, ketosis of other things can happen, which 526 00:21:09,452 --> 00:21:11,858 is why we recommend these s day rules 527 00:21:12,009 --> 00:21:14,868 to stop the s jolt 2 temporarily drink 528 00:21:14,868 --> 00:21:15,368 periods 529 00:21:15,742 --> 00:21:16,775 of acute illness, 530 00:21:17,331 --> 00:21:19,896 but the important thing is remember to restart 531 00:21:20,032 --> 00:21:21,962 because 1 of the problems we have with 532 00:21:21,962 --> 00:21:24,439 the implementation of these therapies is they get 533 00:21:24,439 --> 00:21:26,436 stopped, let's say we're an acute all, but 534 00:21:26,436 --> 00:21:28,927 they don't get restarted. So we have to 535 00:21:28,927 --> 00:21:31,560 remember it to restart these agents once a 536 00:21:31,560 --> 00:21:33,955 person's recovered, usually about a week of recovery 537 00:21:33,955 --> 00:21:35,950 is enough, and they can go back on. 538 00:21:36,604 --> 00:21:38,778 The other thing that came up with can 539 00:21:38,917 --> 00:21:41,171 frozen and the canvas cardiovascular 540 00:21:42,027 --> 00:21:45,138 outcome portfolio of trials was at increased risk 541 00:21:45,138 --> 00:21:45,877 of amp. 542 00:21:46,667 --> 00:21:48,576 Of that has not been seen in any 543 00:21:48,576 --> 00:21:50,722 of the other trials, and it may have 544 00:21:50,722 --> 00:21:52,551 been a play of chance, but that said, 545 00:21:53,267 --> 00:21:56,543 it's still a good practice to remember to 546 00:21:56,543 --> 00:21:59,412 advise patients about good foot care. And again, 547 00:21:59,730 --> 00:22:01,563 this is why these are not fire forget 548 00:22:01,563 --> 00:22:04,684 therapies part of grooming a patient on these 549 00:22:04,684 --> 00:22:06,830 agents should be taking their shoes and socks 550 00:22:06,830 --> 00:22:08,977 on. It's very simple to look at their 551 00:22:08,977 --> 00:22:11,203 feet, and that's why we need to do 552 00:22:11,203 --> 00:22:11,703 clinical 553 00:22:12,236 --> 00:22:12,952 evaluations as well. 554 00:22:13,604 --> 00:22:17,680 But with daily foot, self exams and regular 555 00:22:17,680 --> 00:22:21,536 foot exams at, clinical visits, it's very rare 556 00:22:21,596 --> 00:22:23,948 amp computations, And then finally hypoglycemia 557 00:22:24,807 --> 00:22:27,603 only rarely occurs, and usually, this is in 558 00:22:27,603 --> 00:22:30,574 people with well preserved G r But again, 559 00:22:30,653 --> 00:22:33,048 we sometimes have to back off other glucose 560 00:22:33,048 --> 00:22:33,607 soaring agents, 561 00:22:34,405 --> 00:22:36,481 and I'll reiterate the caution if someone is 562 00:22:36,481 --> 00:22:39,410 on insulin to not completely eliminate it 563 00:22:40,086 --> 00:22:42,395 maintain at least 10 units or so long 564 00:22:42,395 --> 00:22:45,284 acting insulin to help prevent keto. 565 00:22:46,217 --> 00:22:49,103 Wow, doctor total such a wealth of information 566 00:22:49,103 --> 00:22:51,201 there? Well, I, you know, I I particularly 567 00:22:51,261 --> 00:22:52,619 wanted to come back to that point you 568 00:22:52,619 --> 00:22:55,655 made about statins as compared to ST2 569 00:22:55,655 --> 00:22:57,529 and inhibitors errors and how These are really 570 00:22:57,669 --> 00:22:59,509 medications where we need to monitor patients and 571 00:22:59,509 --> 00:23:01,669 bring them back and and do a little 572 00:23:01,669 --> 00:23:03,750 bit more hand holding with respect to the 573 00:23:03,750 --> 00:23:05,910 medication and Everything you outlined there is is 574 00:23:05,910 --> 00:23:07,655 such a road map of doing so that 575 00:23:07,734 --> 00:23:08,765 I think I might need to print it 576 00:23:08,765 --> 00:23:10,272 out and put it on the walls. My 577 00:23:10,272 --> 00:23:11,859 office or something like that. It was that 578 00:23:11,859 --> 00:23:15,625 incredible. That wonderful background aside, potential applications and 579 00:23:15,997 --> 00:23:17,924 indications for S 2 inhibitors 580 00:23:18,771 --> 00:23:20,095 continue to be areas of 581 00:23:20,453 --> 00:23:20,953 active 582 00:23:21,329 --> 00:23:24,037 investigation and recent trial examining the value of 583 00:23:24,037 --> 00:23:24,537 s 584 00:23:25,152 --> 00:23:25,551 inhibitors, 585 00:23:26,028 --> 00:23:28,338 specifically flows and with the recent impact of 586 00:23:28,338 --> 00:23:28,896 my trial. 587 00:23:29,470 --> 00:23:32,190 As 1 example, but many others. Doctor Total, 588 00:23:32,349 --> 00:23:34,750 could you share your perspective on next steps 589 00:23:34,750 --> 00:23:37,070 for investigation of ST2 590 00:23:37,070 --> 00:23:39,483 war 1 as you had mentioned already? And 591 00:23:39,483 --> 00:23:42,137 questions we should be thinking about as these 592 00:23:42,275 --> 00:23:45,066 research in this field be. Well, I think 593 00:23:45,784 --> 00:23:48,097 3 things. 1, I think we really need 594 00:23:48,097 --> 00:23:51,230 to move much more ex sleeve of evidence 595 00:23:51,230 --> 00:23:51,730 to 596 00:23:52,190 --> 00:23:54,830 implementation because we have these highly effective therapies 597 00:23:54,830 --> 00:23:57,570 that truly do state life and kidneys. But 598 00:23:57,803 --> 00:23:59,633 they're being markedly under underutilized. 599 00:24:00,508 --> 00:24:02,735 That's a very active area of investigation. There 600 00:24:02,735 --> 00:24:04,190 are multiple barriers 601 00:24:04,819 --> 00:24:07,776 everything from the more complex clinical mandates, which 602 00:24:07,776 --> 00:24:10,194 that we just talked about to cost 603 00:24:10,813 --> 00:24:11,313 to 604 00:24:11,932 --> 00:24:13,850 education of clinicians and patients, 605 00:24:14,503 --> 00:24:16,810 And the other thing too is health care 606 00:24:16,810 --> 00:24:19,299 systems support for doing this kind of care 607 00:24:19,674 --> 00:24:22,856 because these really aren't 15 minute visits, 608 00:24:23,269 --> 00:24:25,742 and we haven't really been resourced to give 609 00:24:25,742 --> 00:24:26,801 this more comprehensive 610 00:24:27,258 --> 00:24:30,345 care. And so that's a real paradigm shift 611 00:24:30,464 --> 00:24:32,845 and it hasn't been very well addressed or 612 00:24:32,845 --> 00:24:33,163 supported. 613 00:24:33,877 --> 00:24:35,306 More so with for, 614 00:24:36,021 --> 00:24:37,870 advanced heart clinic programs 615 00:24:38,418 --> 00:24:40,964 but not so much, I think in general 616 00:24:40,964 --> 00:24:43,692 clinical practice of cardiology or ne, 617 00:24:44,465 --> 00:24:46,315 and I think this needs to be an 618 00:24:46,315 --> 00:24:48,634 area where we really do put a lot 619 00:24:48,634 --> 00:24:52,075 more emphasis and resources because people only benefit 620 00:24:52,075 --> 00:24:53,755 from treatment say or see, and we need 621 00:24:53,755 --> 00:24:54,634 to do a better job. 622 00:24:55,289 --> 00:24:56,587 And then with regard to 623 00:24:56,965 --> 00:24:59,519 implementation, you've probably all heard about the phenomena 624 00:24:59,519 --> 00:25:00,259 at clinical 625 00:25:00,717 --> 00:25:02,951 inertia, which is where we sort of gl 626 00:25:02,951 --> 00:25:05,759 gag around starting these meds and trying to 627 00:25:05,759 --> 00:25:07,754 get the back every 3 or 4 months 628 00:25:07,754 --> 00:25:09,510 and start new med. But especially if you 629 00:25:09,510 --> 00:25:11,480 look at the heart failure outcomes 630 00:25:11,838 --> 00:25:13,831 We know that, whether we look at a 631 00:25:13,831 --> 00:25:15,687 heart failure population or a Ct 632 00:25:16,303 --> 00:25:17,339 population, in particular, 633 00:25:17,818 --> 00:25:19,971 the heart failure outcomes occur early, 634 00:25:20,543 --> 00:25:23,426 they're frequent in both of those populations, and 635 00:25:23,642 --> 00:25:26,764 we see almost an immediate benefit on reducing 636 00:25:26,820 --> 00:25:27,638 risk of 637 00:25:27,947 --> 00:25:28,685 heart failure 638 00:25:29,138 --> 00:25:31,201 hospitalization or urgent visits. So we can't wait 639 00:25:31,201 --> 00:25:33,741 6 months to get everybody on board here. 640 00:25:33,979 --> 00:25:36,301 And this is again, white not fire forget 641 00:25:36,301 --> 00:25:39,194 therapy. We need to rapidly escalate therapies. 642 00:25:39,571 --> 00:25:42,203 What that means, I think it also needs 643 00:25:42,203 --> 00:25:44,676 research, You know, what therapies when how fast. 644 00:25:45,408 --> 00:25:48,029 But, you know, that is important because these 645 00:25:48,029 --> 00:25:50,412 patients are very high risk of death, and 646 00:25:50,412 --> 00:25:52,397 they die of heart failure, Again, whether they 647 00:25:52,397 --> 00:25:54,242 come through the heart failure portable or the 648 00:25:54,322 --> 00:25:57,035 Ck portal. That's what takes both groups of 649 00:25:57,035 --> 00:25:58,631 patients out, but they're not really both groups 650 00:25:58,631 --> 00:26:01,757 of patients. They're largely the same people. Just 651 00:26:01,757 --> 00:26:03,351 depends on which portal you come in through. 652 00:26:03,510 --> 00:26:05,503 So for example, in light practice, most people 653 00:26:05,503 --> 00:26:07,575 have an E afar ejection fraction the same, 654 00:26:07,734 --> 00:26:10,065 both less than 30. That a heart failure 655 00:26:10,065 --> 00:26:12,464 patient with loan G in a Ck patient 656 00:26:12,464 --> 00:26:14,785 with low ejection fraction. Let's really ample. 657 00:26:15,424 --> 00:26:17,585 And so we need to recognize the enormous 658 00:26:17,585 --> 00:26:19,907 risk of death and that we have treatments 659 00:26:19,907 --> 00:26:22,602 that very quickly reduce that risk substantially. 660 00:26:23,157 --> 00:26:23,657 So 661 00:26:24,029 --> 00:26:26,982 implementation and then no inertia end much more 662 00:26:26,982 --> 00:26:27,482 rapid 663 00:26:28,019 --> 00:26:28,976 escalation of therapy. 664 00:26:29,455 --> 00:26:31,847 And then finally, back to the science again, 665 00:26:32,087 --> 00:26:34,342 we're learning a lot more about how S 666 00:26:34,480 --> 00:26:36,210 2 inhibitors work and how we 667 00:26:36,726 --> 00:26:39,666 stumbled on this almost by accident although, not 668 00:26:39,666 --> 00:26:42,129 completely because when we first gave flu into 669 00:26:42,129 --> 00:26:43,615 those routes. So we 670 00:26:44,130 --> 00:26:46,614 envisioned that at least the gl mer hem 671 00:26:46,908 --> 00:26:48,416 if that could occur, although I don't think 672 00:26:48,416 --> 00:26:50,400 we imagined it would have such profound effects 673 00:26:50,400 --> 00:26:51,669 on heart failure. But that said, 674 00:26:52,479 --> 00:26:54,872 Some of the mechanisms that we're discovering really 675 00:26:54,872 --> 00:26:56,786 could lead us to new targets that might 676 00:26:56,786 --> 00:26:59,178 even be safer and more effective. So for 677 00:26:59,178 --> 00:27:01,911 example, if we could target torque directly 678 00:27:02,224 --> 00:27:03,984 then we might not have a lot of 679 00:27:03,984 --> 00:27:06,464 side center real into Across Area. 680 00:27:07,265 --> 00:27:09,160 Doctor Total. Thank you so much for 681 00:27:09,518 --> 00:27:12,146 noting everything that you just mentioned, I think 682 00:27:12,146 --> 00:27:15,093 that your points are so well taken particularly 683 00:27:15,093 --> 00:27:17,721 with regards to mentioning the barriers to implementation 684 00:27:17,721 --> 00:27:20,445 of this science when all of the investigations 685 00:27:20,445 --> 00:27:22,118 are moving so quickly and we're learning so 686 00:27:22,118 --> 00:27:24,190 much about these drugs. I think it's really 687 00:27:24,190 --> 00:27:25,327 just such an important 688 00:27:25,797 --> 00:27:27,782 perspective to maintain that we really need to 689 00:27:27,782 --> 00:27:29,846 figure out how to figure out how to 690 00:27:29,846 --> 00:27:32,387 get these medications to patients. So thanks so 691 00:27:32,387 --> 00:27:34,950 much for mentioning that. Now given everything that 692 00:27:34,950 --> 00:27:36,944 we discussed doctor Tu, would you please be 693 00:27:36,944 --> 00:27:38,380 able to summarize for our audience, some of 694 00:27:38,380 --> 00:27:39,518 the key takeaways 695 00:27:39,895 --> 00:27:42,846 that our listeners should remember regarding S t 696 00:27:42,846 --> 00:27:43,165 inhibitors? 697 00:27:44,137 --> 00:27:46,232 Well, I think these really are transformative 698 00:27:46,689 --> 00:27:47,189 therapies, 699 00:27:47,805 --> 00:27:48,943 and they address 700 00:27:49,400 --> 00:27:52,351 very important risks in patient populations. 701 00:27:52,923 --> 00:27:55,861 For example, in heart failure particulate preserved ejection 702 00:27:55,861 --> 00:27:58,561 fraction in chronic kidney disease, which were rather 703 00:27:58,561 --> 00:27:59,061 hopeless 704 00:27:59,434 --> 00:28:01,737 conditions until these agents appeared on the scene. 705 00:28:02,229 --> 00:28:04,698 And now we truly have drugs that save 706 00:28:04,698 --> 00:28:06,450 lives hearts and kidneys. And I think we 707 00:28:06,450 --> 00:28:08,463 need to have a sense of urgency 708 00:28:08,839 --> 00:28:11,641 about getting all people on unleash their piece 709 00:28:11,641 --> 00:28:12,436 suzanne benefit. 710 00:28:12,913 --> 00:28:15,457 Also think that as we go forward, we 711 00:28:15,457 --> 00:28:17,762 probably should do a better job of if 712 00:28:17,762 --> 00:28:18,659 you will clinically 713 00:28:19,670 --> 00:28:21,615 patients for which therapy 714 00:28:22,146 --> 00:28:23,281 and prioritizing 715 00:28:23,654 --> 00:28:25,265 those that have the greatest benefits. 716 00:28:25,717 --> 00:28:28,495 For example, with regard to ST2 717 00:28:28,495 --> 00:28:28,995 inhibitors 718 00:28:29,383 --> 00:28:31,522 In addition to getting them on therapy. I'd 719 00:28:31,522 --> 00:28:33,582 also like to comment that we should take 720 00:28:33,582 --> 00:28:36,927 people off with potential harmful therapies like non 721 00:28:36,927 --> 00:28:39,951 steroid anti inflammatory drugs and proton pump inhibitors, 722 00:28:40,508 --> 00:28:43,930 So please put people on guideline directed medical 723 00:28:43,930 --> 00:28:46,971 therapy, S 2 inhibitors, truly have been a 724 00:28:46,971 --> 00:28:49,763 guest there is life saving for patients who 725 00:28:49,763 --> 00:28:52,315 have very few options here to 4 and 726 00:28:52,315 --> 00:28:54,150 also remember to get rid of the things 727 00:28:54,150 --> 00:28:56,795 that undo the good we're doing. With these 728 00:28:56,795 --> 00:28:59,340 agents such as giving non str inflammatory drugs 729 00:28:59,340 --> 00:29:01,090 which are not good for either heart failure 730 00:29:01,090 --> 00:29:01,965 or kidney disease. 731 00:29:03,174 --> 00:29:05,170 Thanks for really dis it down to these 732 00:29:05,170 --> 00:29:07,665 key takeaways for listeners and putting that clinical 733 00:29:07,724 --> 00:29:09,799 perspective of how to get patients on the 734 00:29:09,799 --> 00:29:11,635 right drugs and off of the wrong 1. 735 00:29:12,447 --> 00:29:14,353 Something that we always like to ask our 736 00:29:14,353 --> 00:29:17,213 guest expert on cardio is, what makes your 737 00:29:17,213 --> 00:29:20,073 heart flutter about S inhibitors and the future 738 00:29:20,073 --> 00:29:21,502 for science in this field? 739 00:29:22,714 --> 00:29:25,451 Well, I think that the S 2 inhibitors 740 00:29:25,670 --> 00:29:28,947 really burst open an entirely new era for 741 00:29:28,947 --> 00:29:31,160 heart failure and Ck cad. And I think 742 00:29:31,279 --> 00:29:33,192 as I mentioned, we have a lot to 743 00:29:33,192 --> 00:29:35,981 worry about how to implement and apply these 744 00:29:35,981 --> 00:29:36,481 therapies, 745 00:29:36,938 --> 00:29:38,713 how to learn from the mechanisms 746 00:29:39,663 --> 00:29:42,215 involved in S 2 heart and kidney protection 747 00:29:42,215 --> 00:29:43,811 to make better treatments, 748 00:29:44,449 --> 00:29:46,283 but the other thing it did is that 749 00:29:46,283 --> 00:29:48,437 ushered in a new era of interest in 750 00:29:48,437 --> 00:29:51,259 heart failure Ck that's really unprecedented. 751 00:29:51,792 --> 00:29:54,017 And so in addition to S 2, we 752 00:29:54,017 --> 00:29:56,242 now have other breakthrough therapies? 753 00:29:56,814 --> 00:30:00,805 And a pipeline of therapies that may help 754 00:30:00,805 --> 00:30:03,518 to ratchet down residual risk, but then I 755 00:30:03,518 --> 00:30:06,009 just wanna emphasize the other we need to 756 00:30:06,009 --> 00:30:08,406 do is then figure out who gets what 757 00:30:08,406 --> 00:30:11,303 drug does everybody need everything all the time 758 00:30:11,442 --> 00:30:14,013 and get rid of potentially harmful things. But 759 00:30:14,013 --> 00:30:16,985 what makes my heart flutter is that hopeless 760 00:30:17,123 --> 00:30:19,913 diseases have now become very hopeful, and these 761 00:30:19,913 --> 00:30:22,716 are all really good problems to have? To 762 00:30:22,716 --> 00:30:24,781 have therapies so that we can even ask 763 00:30:24,781 --> 00:30:25,678 these questions 764 00:30:26,448 --> 00:30:28,060 about order therapies 765 00:30:28,592 --> 00:30:30,125 combination of therapies, ph, 766 00:30:31,213 --> 00:30:33,696 implementations I welcome the challenges, and I'm so 767 00:30:33,696 --> 00:30:36,006 glad I can go to clinic now and 768 00:30:36,006 --> 00:30:37,918 say, we have treatment. We have treatment that 769 00:30:37,918 --> 00:30:40,330 saves lines hearts and kidneys and be really 770 00:30:40,467 --> 00:30:40,967 excited 771 00:30:41,278 --> 00:30:44,624 and patience are so grateful, and especially in 772 00:30:44,624 --> 00:30:45,283 ne mythology, 773 00:30:45,978 --> 00:30:48,946 many of them used to come feeling so 774 00:30:49,561 --> 00:30:52,452 disillusioned. And now it's a completely different vibe, 775 00:30:52,692 --> 00:30:56,308 and it's so wonderful to see them happy 776 00:30:56,448 --> 00:30:58,366 about the idea that they could actually get 777 00:30:58,366 --> 00:31:01,164 better, not just continue to slowly get worse. 778 00:31:01,877 --> 00:31:04,256 Doctor total your passion for the fields and 779 00:31:04,256 --> 00:31:06,317 patient care really shines through, and it's been 780 00:31:06,317 --> 00:31:08,554 such a master class learning from you about 781 00:31:08,633 --> 00:31:09,768 S inhibitors 782 00:31:10,142 --> 00:31:11,356 from the basic biology 783 00:31:11,729 --> 00:31:13,873 and beyond. I was just thinking back to 784 00:31:13,873 --> 00:31:16,192 when we first learned about Cl inhibitors during 785 00:31:16,192 --> 00:31:18,579 the preclinical years of med school. And at 786 00:31:18,579 --> 00:31:20,011 that time, I think we just learned about 787 00:31:20,011 --> 00:31:20,988 it as a diabetes 788 00:31:21,363 --> 00:31:23,923 medication, it's just remarkable to see that since 789 00:31:23,923 --> 00:31:25,674 then there's been all of this data for 790 00:31:25,674 --> 00:31:29,015 the cardiovascular effects, the renal protective effects, and 791 00:31:29,015 --> 00:31:31,019 how it's become a pillar of therapy for 792 00:31:31,019 --> 00:31:33,659 both heart failure and chronic kidney disease. And 793 00:31:33,740 --> 00:31:35,819 It really speaks to the fighting advances in 794 00:31:35,819 --> 00:31:37,419 this field to how to help take care 795 00:31:37,419 --> 00:31:39,500 of her patients, which is the ultimate goal 796 00:31:39,500 --> 00:31:41,669 for all of us. In both medicine and 797 00:31:41,669 --> 00:31:43,423 research. And it's really great to see how 798 00:31:43,423 --> 00:31:45,437 it can be done in collaboration with cardiologist 799 00:31:45,654 --> 00:31:47,668 working with ne pathologist and endo 800 00:31:48,378 --> 00:31:51,241 than other physicians and also other health care 801 00:31:51,241 --> 00:31:53,308 professionals. So we really wanna thank you for 802 00:31:53,308 --> 00:31:55,455 taking out time to teach us today and 803 00:31:55,455 --> 00:31:57,774 really sharing your for expertise. I'll definitely have 804 00:31:57,774 --> 00:31:59,522 to listen back to absorb all of the 805 00:31:59,522 --> 00:32:02,302 pearls that you've reviewed and the mechanisms of 806 00:32:02,302 --> 00:32:04,447 action and the biology behind these agents. 807 00:32:05,018 --> 00:32:07,643 Thank you so much. We're really excited to 808 00:32:07,643 --> 00:32:08,836 share this with our listeners. 809 00:32:09,314 --> 00:32:11,835 Well, thanks for including me. It's wonderful to 810 00:32:11,954 --> 00:32:14,582 see the future of cardiology and medicine so 811 00:32:14,582 --> 00:32:16,573 bright is reflected in all of you. 812 00:32:17,210 --> 00:32:17,710 So 813 00:32:18,086 --> 00:32:20,529 go forth and set the world empire, see 814 00:32:21,925 --> 00:32:24,158 Thank you so much for tuning into this 815 00:32:24,158 --> 00:32:27,347 cardio nerds episode. The audio editing for this 816 00:32:27,347 --> 00:32:29,442 episode was performed by me, Cri. 817 00:32:30,629 --> 00:32:32,695 I'm an intern in the Cardio Nerds Academy 818 00:32:32,695 --> 00:32:34,386 and a senior at Boston University. 819 00:32:35,158 --> 00:32:37,223 Check out the episode page for the show 820 00:32:37,223 --> 00:32:39,869 notes and references. Thanks If you found this 821 00:32:39,869 --> 00:32:41,570 episode or the show informative, 822 00:32:42,110 --> 00:32:44,750 please consider subscribing to cardio nerds on your 823 00:32:44,750 --> 00:32:47,164 favorite podcast pop platform and leaving us a 824 00:32:47,164 --> 00:32:47,404 review. 825 00:32:47,965 --> 00:32:49,965 It really helps us spread the word and 826 00:32:49,965 --> 00:32:52,225 further our goal to democrat cardiovascular 827 00:32:53,085 --> 00:32:53,325 education. 828 00:32:53,965 --> 00:32:56,532 Finally, platform This podcast is not meant to 829 00:32:56,532 --> 00:32:57,966 be used for medical advice. 830 00:32:58,524 --> 00:33:00,516 The views is expressed on our show site 831 00:33:00,516 --> 00:33:02,943 do not reflect the opinions or policies 832 00:33:03,478 --> 00:33:04,434 of our employers. 833 00:33:05,231 --> 00:33:09,315 All cardio content is planned, produced and reviewed 834 00:33:09,532 --> 00:33:10,806 solely by cardio nerds. 835 00:33:11,538 --> 00:33:13,231 Stay tuned for more engaging 836 00:33:13,606 --> 00:33:16,073 conversations and exploration in our new and exciting, 837 00:33:16,710 --> 00:33:19,335 upcoming episodes. And now my friends, it's time 838 00:33:19,335 --> 00:33:21,480 to make like an s 2 and split.