S1 Episode 1: Gout and Comorbidities: A Two-Way Relationship

Episode TranscriptThis transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.Kenneth Saag, MD: Hello, I'm Dr Ken Saag. Welcome to Medscape InDiscussion series on gout. Today we're talking about cardiovascular risk and comorbidities in hyperuricemia and gout with our guest Dr Michael Pillinger. Dr Pillinger is professor of medicine and biochemistry and molecular pharmacology at the NYU Grossman School of Medicine.He is a rheumatologist at NYU and the VA New York Healthcare System. Mike is a longtime investigator in inflammation and crystal diseases, including gout. He's the founding director of the NYU Langone Crystal Disease Study Group and co-director of the NYU Gout Treatment Center. Welcome, Michael, to InDiscussion.Good to have you here. What's shaking in New York City these days?Michael Pillinger, MD: It's summer, but the heat's broken, and we're just into August. So the crowds have thinned out, and we're having a nice time.Saag: Let's get into the discussion — there's lots to talk about. What are the comorbidities that we think about with gout? Is it chicken or egg? Do comorbidities lead to gout, or do gout and hyperuricemia lead to comorbidities? That may be the central question that we'll grapple with here.Pillinger: There are a lot of comorbidities in gout to be sure, and we'll talk about the chicken and the egg, but we probably ought to enumerate at least some of them.I'm a fellowship director, and I always tell my fellows when I'm teaching them that even if you think gout is simple, it's not; patients with gout are not simple because they are overlaid with lots of complexity. What are some of these things that they have? Well, they have increased cardiovascular disease (CVD). As we've recently reported, they have increased peripheral vascular disease as well. Not surprising, they have increased kidney disease. They have increased obesity, and I always thought that only went one way, but maybe not. They have hypertension. Studies have shown epidemiologically that if you look at patients with gout, 70%-90% of them are hypertensive.They have increased diabetes. They have metabolic syndrome probably at a rate about double that of the general population, which is an awful lot. There are other things going on that are a little harder to pin down — things happening, for example, in the liver. It's worth noting that people with gout don't just have inflammation when their big toes get swollen. Oftentimes people think they don't have gout because their big toe’s not swollen, but we can find biochemical evidence that they walk around at chronic levels of increased inflammation. There are a lot of things. There might be a couple of benefits, too; I don't know if we'll have a chance to get to that.Saag: Is gastroesophageal reflux disease (GERD) in there? I've heard GERD is often included as one of the things that are associated with gout. Are these things, again, epiphenomenon? These are people that are chronically ill. And because of being chronically ill, they get diuretics, they develop chronic kidney disease (CKD), their serum uric goes up, and then they're prone to gout.Talk to us a bit about that.Pillinger: It's tough. It's one of the key areas of ongoing investigation. When I got involved in doing gout research, I wasn't very interested in the flares. I'm more interested in the flares now than I was before, but then the problem is it's very hard to sort out.It's hard to sort out the epiphenomenon and the causal direction. Usually, if you ask me about the chicken and the egg, I say it's both. At least for some things. You already mentioned kidney disease. Kidney disease, clearly at minimum, results in increased uric acid that raises the predisposition to gout, tophaceous gout, and increase in gout severity.Saag: I'm drawn back to an experiment many years ago by one of the nephrologists — Richard Johnson's team looking at a particular rat in which they made the rat hyperuricemic and the rat developed renovascular hypertension, and then they gave it allopurinol and reversed it.Pillinger: And then they reversed it again. You flip the switch in multiple directions. There's this interesting evolutionary question about why we are hyperuricemic, maybe not why we have gout. If you're a bit nerdy like me, you would know that your cocker spaniel has a uric acid level of about 1 mg/dL, and we have a uric acid level of about 4.5-5.0 mg/dL, and the levels in gout patients are way higher.And that's because we lost this enzyme called uricase about 15 million years ago, and evolution was gunning for this enzyme, Ken. It knocked it out at least four times, but it only knocked it out in primates. And the interesting thing is that at the time it knocked it out in primates, these primates were eating low-salt diets, and they were trying to stand up.As I said to medical students today, there's some thought, partly from Johnson's group, that high urates helped raise blood pressure when it was low and when you couldn't perfuse. And I've got this image of a gorilla standing up in a tree pounding its chest.Saag: The dinosaur Sue in the Field Museum in Chicago, they think she had gout. It's curious how the enzyme deficiency jumped around. Dalmatians seem to have high urate as well, and it's not all dogs. Let's get back to this issue about cause or effect, and you would think that if there is a causal relationship if hyperuricemia is possibly causal.I gave the example in the rat and mentioned that allopurinol might work in the rat. This is the great thing about gout: We know what causes it. It's uric acid, and if you lower uric acid, say with a xanthine oxidase inhibitor like allopurinol, you can turn it around.In terms of the Bradford Hill criteria, reversibility is there as one of the causal things. Can you just give everybody a xanthine oxidase inhibitor and make their blood pressure better? What are the data on that?Pillinger: Well, we should probably treat essential hypertension in everybody with allopurinol. There's a great study in adolescents who were hypertensive and hyperuricemic, and they were given allopurinol.Saag: In very early hypertension: absolutely. And we tried to do that in adults — in young adults — and our study was largely negative. Now, those adults didn't do everything we asked them to do. They didn't wear their cuffs (you have to wear an ambulatory blood pressure cuff), and they didn't take their medicine. So it might have been some experimental design issue. But it was largely a null study, although interestingly, we did see improvement in flow-mediated vasodilation in the group while they were on allopurinol, suggesting that maybe something physiologically was going on when we measured it.But then there are data from the Mendelian randomization studies. What about those? Are those helpful? They don't seem to support this association at all.Pillinger: It's complicated, and we should probably distinguish, at least based on the data, between asymptomatic hyperuricemia and gout.And I think another thing we ought to think about is most of our gout patients — maybe not the patients in your study — and we were able to see a similar thing with flow-mediated dilation. But most of our gout patients are older, and they probably have hard arteries by the time they've had gout and all the comorbidities for 65 years.Now, Mendelian randomization, that's tough. For the audience, Mendelian randomization tries to get past all the comorbidities and complications by evening out the populations using their genetic bases. And at least in hyperuricemia, when you do that, you lose a lot of the evidence that there's an effect.Honestly, Ken, I'd love to know what you think.Saag: Well, I'm also troubled by a series of studies mostly looking at the kidney association, where we looked at people with diabetic nephropathy and other things, and there was really no benefit of reducing urate in those patients on their kidney function, and that was discouraging.Pillinger: I think the evidence is grimmer in folks with asymptomatic hyperuricemia. For example, the CKD-FIX trial looked at this. There are problems with such studies, of course. one of which was that, in that study, the urate wasn't followed very well. It's interesting that a number of studies by nephrologists and cardiologists that have tried to look at effects of allopurinol have not necessarily enrolled hyperuricemics.Saag: And then there are some data with pegloticase (pegylated recombinant uricase), which is about the most powerful drug we have for lowering urate. It seemed to have a subtle effect on blood pressure. What did you think of those data?Pillinger: Remember that enzyme those primates, our friends, lost?They lost uricase, and pegloticase is a way of replacing the uricase. And uricase turns out to be very potent. You give this drug, and you watch a patient whose urate is 12 mg/dL go to 0.3 mg/dL by the next day. That raises its own curious issues. But there was a population study, and it took those older patients with gout who were probably vascular resistant to subtle changes, and it tanked their urate for a period of time.On a population basis at least, you could see a decline in systolic diastolic and mean arterial pressure by the end of the study.Saag: So maybe you need to annihilate urate, which is not going to happen forever because we just can't continue that drug indefinitely for a lot of reasons.A couple years ago — I think you were there — there was a meeting in Europe, and there was a big panel discussion on this topic. And one of the conclusions was that we really didn't need to do more studies to look at reducing urate for nongout benefit — that we'd basically shown that it didn't work.It sounds like you have some questions still, as I think I do, about how good some of these negative studies are, and maybe there are some signals that we should pay attention to.Pillinger: There have been a couple of recent studies, Ken, that lean the other way.There is some evidence among gout patients, but not among hyperuricemics, that lowering urate may preserve renal function.Saag: Let's talk about that because there are some interesting data now looking at the concern of gout and particularly gout flares on CVD. Do you want to talk about that?That's really been pivotal in how we think about flares, and it may possibly explain some of the cardiovascular mortality signals that we're seeing with some of these very potent urate-lowering drugs.Pillinger: The point I think you're making there is if you use a potent urate-lowering drug and you don't manage it properly, you may increase risk for flares.There have been two arms of seminal studies in the last year or so, a lot of them out of the Nottingham group. One of them was an emulated target trial for effective allopurinol on long-term cardiovascular mortality, and that was relatively recent, and it showed a benefit among gout patients.I don't think the scope of the benefit was overwhelming, but it was unequivocal and significant. Now, it was not a prospective trial. None of these are prospective trials. But there's fascinating work out of this group. Rheumatologists know that when you start to lower uric acid, you get more flares for something in the neighborhood of 6 months.Saag: That's hard for patients to appreciate, isn't it? And it's one of the reasons we see nonadherence to urate-lowering drugs. You have to try to prophylax, but it's sometimes hard to do.Pillinger: They come back to you and say, "Doc, what have you done to me? I'm never taking this medicine again."And you're trying to convince them to wait it out, right? But probably means you didn't prophylax adequately. The really cool thing about these studies was the idea (it's built into the studies, not necessarily stated) that in the setting of a flare or this burst of inflammation, whatever's happening in the joint may be happening in the vasculature, and the patient is in a window of risk.And it looks like up to about 120 days, there's an increased risk for both MI and stroke — a near doubling.Saag: Didn't they have a companion paper also showing an increased risk for thromboembolic events, DVTs and the like?Pillinger: Yes, and they tried to have a look at prophylaxis basically.And in a study, at least one study, prophylaxis with colchicine seemed to protect against this effect in the context of protecting against flares. Colchicine has a muddled history but a long track record, spanning a decade or more, of potentially lowering MI, not just in our patients but in the general population.It wasn't too surprising. And in another study, nonsteroidal anti-inflammatory drugs made this worse, even though they prevented flares.Saag: Let's change gears because there are a lot of drugs out there now that we're using for other reasons that might benefit gout, for example, drugs for CVD.I'm thinking about losartan, for example, and SGLT2 inhibitors. And there are a lot of questions around, obviously, GLP-1 inhibitors. Those are all exciting classes of drugs that may affect gout and hyperuricemia. Do you want to comment on that?Pillinger: I will, although I suspect you're more of an expert in this area than I am.But to go back to the idea that our gout patients have many comorbidities, and those need to get treated. it seems like common sense to me that you might as well pick comorbidity treatments that might do double duty and help you with your gout patient. You gave some of the key examples.Losartan's one of the early ones. Always seems like a no-brainer, right? The primary care docs love hydrochlorothiazide. They're not wrong: It's cheap and effective, and it keeps us in business because everybody's urate goes up and they get gout. But why not give a hypertensive that lowers urate? I would never hold Lasix in a patient with heart failure, but we have substitutable drugs in a lot of cases where we can derive a benefit.What do you think about the SGLT2s?Saag: Those drugs have a uricosuric effect as well as a glucosuric effect. If you can tolerate them, they're not easy to take. You're urinating a lot. There are Candida concerns, and even some fasciitis has been described.They can be pivotal for diabetes and heart failure, and they seem to be good for gout. We've seen that. I've been curious about the GLPs, and so far the data look equivocal. Maybe initially you might get a little worse, possibly you start eating more protein or you're having fluid shifts when you start losing weight more rapidly. But then the meta-analyses suggest a very modest effect of these agents that could be beneficial as well. Obviously, with gout, you have to lose a lot of weight. You have to lose 20 pounds to drop your serum urate by 1 mg/dL. It’s a difficult thing to do.Pillinger: I don't think, at this point at least, that these drugs and other drugs for hypertension, for example, calcium channel blockers, are a lot better than beta-blockers, which make things worse. They're not going to be the solution for gout. But good clinical practice is, to me, setting a neat table.If you can choose these for patients who need something anyway, you'll get your patient closer to needing less treatment from us, and that's reasonable. We may come to the time where some of these things will fully do dual duty. I don't think we're quite there yet.Saag: What do you advise your patients with gout about CVD risk protection?We probably work very closely with our primary care colleagues who manage a lot of gout anyhow, but for the patients you follow, what are your general strategies?Pillinger: Number one, work with the primary care docs and cardiologists, and fix all the comorbidities in a way that will help the gout.That's the egg to the chicken part. When it comes to treating gout, I personally believe there probably is at least some modest benefit in getting the urate under control, and I use that to promote compliance. I tell my patients, "Maybe you're not just treating that flare twice a year. Maybe you're helping reset your metabolic state. Maybe you're lowering your CVD. Would you really want to wait five years for me to tell you we've proven that, and five years you couldn't have taken your gout medicine?" I think that's important. The question I'm going to ask you about, Ken, though, is what's your take in this setting on colchicine? I tend to go along with colchicine.Saag: I've started to use it longer. From the data out of the UK, including the effects of flares, it's terrifying to see the increased MIs. I have gotten more aggressive with the longer course of colchicine. Eventually maybe someday if they're cheaper, the interleukin-1 inhibitors, and maybe someday we'll have oral ones, that'd be great.Mike, in the last bit here, I want you to bring us back to where we started. I want to ask you the thing that we get asked a lot and that we, you and I both think about, and we know our colleagues, particularly our Japanese colleagues, have guidelines around this. It's the issue of asymptomatic hyperuricemia, and not all hyperuricemia is asymptomatic, and you sometimes find deposits of gout with advanced imaging that you didn't even know people had.Some of them do have gout, it just hasn't presented clinically. But let's assume that that's not the case. Do we have enough data to treat asymptomatic hyperuricemia? We can look at the Japanese guidelines; what if you're over 9? They recommend you treat it. Do you do that?Pillinger: Okay, I'll fess up. I don't do that, but you can ring my personal bell somewhere upward of 12.Saag: Me too. Thanks for that confession because I'm the same. Anybody who's over 12, I'd lower their serum urate. I don't think that's a good thing at all.Pillinger: I just think, Ken, what I said is, we're going to regret when we discover that those sky-high urates weren't good for you, and we could've fixed it.Saag: This has really been a great discussion. I want to thank you so much. It's been wide-ranging talking about the epidemiology and how we think about causal relationships, the uncertainty of hyperuricemia and its effects on heart disease, kidney disease, hypertension, some data in favor, some not, and then this issue of what to do with people that don't have gout but have high serum urate.And some of the exciting new things about our new therapies for treating heart disease and diabetes and weight that may affect gout. A lot of great things going on in the field, and lots of new drugs under development. I appreciate your time today, and great to catch up again.Pillinger: It's very exciting and a real pleasure to spend time with you.ResourcesGout and PseudogoutGout: Global Epidemiology, Risk Factors, Comorbidities and Complications: A Narrative ReviewThe Fifth Element: Is Vascular Dysfunction an Intrinsic Feature of Gout?Hyperuricemia Induces a Primary Renal Arteriolopathy in Rats by a Blood Pressure-Independent MechanismThe Environment and Disease: Association or Causation?Effect of Allopurinol on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension: A Randomized TrialExpert Consensus and Evidence-Based Recommendations for the Assessment of Flow-Mediated Dilation in HumansReading Mendelian Randomisation Studies: A Guide, Glossary, and Checklist for CliniciansEffects of Allopurinol on the Progression of Chronic Kidney DiseasePegloticase Treatment Significantly Decreases Blood Pressure in Patients With Chronic GoutTreat-to-Target Urate-Lowering Treatment and Cardiovascular Outcomes in Patients With GoutRisk of Venous Thromboembolism With Gout FlaresCardiovascular Events in Patients With Gout Initiating Urate-Lowering Therapy With or Without Colchicine for Flare Prophylaxis: A Retrospective New-User Cohort Study Using Linked Primary Care, Hospitalisation, and Mortality DataComparative Cardiovascular Safety of Nonsteroidal Anti-Inflammatory Drug Versus Colchicine Use When Initiating Urate-Lowering Therapy Among Patients With Gout: Target Trial EmulationsUric Acid as a Risk Factor for Chronic Kidney Disease and Cardiovascular Disease - Japanese Guideline on the Management of Asymptomatic Hyperuricemia