A Q&A with Sidhartha Sinha, MD
We sat down with Sidhartha Sinha, MD, Assistant Professor of Medicine in Gastroenterology and Hepatology at Stanford University, to discuss his work evaluating the potential for the statin drug class, commonly prescribed to lower low-density lipoprotein (LDL or “bad cholesterol”), to treat stricturing Crohn’s disease. Strictures are narrowed areas of the intestine caused by inflammation and tissue thickening, and they can cause bloating, abdominal pain, and even death. Stricturing Crohn’s disease is the main driver of hospital admissions. Nearly half of patients with Crohn’s disease will need bowel resection surgery within ten years of diagnosis due to strictures.
Recent evidence from your lab suggests that statins — prescription medications that lower low-density lipoprotein cholesterol and reduce the risk of heart attacks and strokes — may be an effective treatment option for stricturing Crohn’s disease. What is exciting about this approach, how are you studying it, and what would this mean for people with Crohn’s disease?
What excites me the most about this is that it’s clearly one of the great unmet needs in Crohn’s disease — strictures are one of the most severe and common complications. As of right now, we don’t have any therapeutics for it. What my group found was that in a couple of retrospective studies, patients who use statins and have Crohn’s disease go on to develop significantly less strictures. That was an interesting finding for us.
What my lab does is try to move beyond associations we find in retrospective studies and understand some of the biology, to see if something that can actually be translated prospectively into helping patients.
The team leading the Crohn’s Disease Therapeutics focus area at Helmsley — Jessica Langer and Aaron Bender — recognized that one of the really exciting things about statins is that they are already FDA approved. Tens of millions of people are on this drug.
With Helmsley support, we’re now doing a prospective study in collaboration with a group in Los Angeles to look at patients who are going to have surgery for stricturing Crohn’s disease, and randomizing these patients to a placebo or to a statin. They’ll take this for two weeks before their surgery, and, six to 12 months down the road, they’ll be assessed with imaging to see if we notice between the group that received statins and those that received a placebo.
We chose this kind of model, with patients who are having surgery, primarily because these strictures develop over long periods of time — over years or even decades. A clinical trial with those kinds of lengthy outcomes is nearly impossible. But we also know that strictures come back after they are surgically removed, and we can use known recurrence rates to test the effects of statins. In true collaboration with the team at Helmsley, we were able to develop this promising design. And there are many other ways that we can explore this even further. We’re looking at the biology behind it. We’re going to be analyzing tissue specimens from the patients to understand how statins are preventing stricture recurrence – we think it’s independent of the cholesterol-lowering effect – and if there are biomarkers that might help predict who may or may not respond to the therapy.
You say the effect may be independent of the usual cholesterol-lowering use of statins, so what might the mechanism be for statins in treating strictures? And is there interest in using statins in other conditions that involve fibrosis?
That is one of the things that we want to investigate deeply is: what is it about the statins? We see from the data is that the reduction in risk of strictures is independent of patients’ cholesterol levels, so what might be driving a change in the trajectory of developing structures in Crohn’s disease? With a lot of the multiomic outputs that we’ll be looking at, we’ll be able to see what the key drivers are.
And we absolutely want to use statins for other conditions. In fact, early on, my group and others had also found that statins seem to be beneficial in a disease that’s very much related to inflammatory bowel disease called primary sclerosing cholangitis, or PSC. That’s a fibrotic disease as well. We’re not certain if the biology is the same, but one thing we know about statins is they work by several different mechanisms — that is, there’s a pleiotropic mechanism of action. We have hypotheses for their mechanism in IBD and PSC, based on the biology that is known about statins in other diseases, that they could be anti-inflammatory, they could be antifibrotic, they could modulate the microbiome and the metabolome, in ways that can reduce inflammation and fibrosis.
Considering that statins are widely prescribed and have a known safety profile, what evidence is needed to recommend them as a therapeutic option for people with Crohn’s disease?
That’s the real challenge. Statins are very safe drugs, but no one wants to be on a drug that may not provide them benefit. Trying to understand which populations might benefit most is going to be critical. Now, we’re not going to be able to answer these questions with our study.
The wonderful thing about the Helmsley program is that we get a chance to collaborate and meet people who are also very much interested in these unmet needs. We’re already in the process of thinking about additional trials to improve patient benefit with other investigators. The most likely population is patients that already have a primary indication to start a statin. If your LDL is 200, you should probably be on a medication to lower your cholesterol. In a patient with IBD and an abnormal lipid panel, statins seem to be a very reasonable choice with the possibility of multiple benefits.
What have you learned from patients in these studies?
What has been heartening is patients’ willingness to participate in studies like this. I’ve done studies with pharmacologic interventions, studies with dietary interventions, and studies in diagnostics as well. Seeing patients willing to do something that’s inconvenient and may not offer any direct benefit to them, but they are nonetheless willing to engage with our protocols and our studies, has been really amazing and speaks to their generosity.
My group, and other investigators, are trying to identify what are the biggest needs. I trained in a program called Biodesign at Stanford, which is the application of medical technology to improve health. One of the key things that was drilled into us in that year-long fellowship was the importance of spending the upfront time in understanding the need, validating that need before you go on to try to develop solutions. While the Biodesign program is largely for people who are developing technologies, I’ve sort of taken that mindset in how I design my research program.
These are all some of the most acute needs for patients, the research that we work on in diet and nutrition and in stricturing Crohn’s disease
What have your grants with Helmsley led to in your career?
I’ve been fortunate to have been working with the Crohn’s team at Helmsley now for over 6 years. Helmsley is unique as a funder in the level of collaboration that they engage with investigators. I truly feel like we have partners in trying to address these needs.
With my first project with the Prevention team around diet, it was a wonderful process of iterating and designing the grant that ultimately led to something that I could not have done on my own. I think patients ultimately benefited from that. Engaging all the stakeholders involved, like patients and so many other IBD doctors and researchers in the field — when you do that, you ultimately end up with a study that can hopefully be more meaningful to patients.
