December 3-6, 2020; Virtual; Day #1 Highlights – Draft

While we miss speaking to researchers, hearing Q&A, and seeing our friends in sunny Los Angeles, we thoroughly enjoyed WCIRDC’s virtual conference space. See below for a snapshot and read on for our top highlights from Day #1…

Top Five Highlights

1. Untangling the Interaction Between COVID-19 and Diabetes Pandemics: Insights on Mechanism, Epidemiology, and Patient Care

Dr. Paul Zimmet (Monash University, Australia) and Professor Stefan Bornstein (University Clinic Dresden, Germany) drew our attention to the intricate and convoluted web of interactions between COVID-19 and diabetes pandemics, from the level of molecular biology all the way to the scale of epidemiology. Now nearly nine-months into the coronavirus pandemic, the tight association between diabetes and severe COVID-19 outcomes and mortality has been well-established – at least 20% of patients with severe COVID-19 have diabetes as reported in most large population studies. A public health report from England (recently published in The Lancet Diabetes & Endocrinology) established that individuals with type 2 diabetes were at two-fold greater risk of developing severe COVID-19 compared to those without diabetes; patients with type 1 diabetes were at over three-fold greater risk. In this critically relevant symposium jointly held by The Lancet Diabetes & Endocrinology and WCIRDC, Drs. Zimmet and Bornstein reviewed the mechanism by which COVID-19 susceptibility is conferred in diabetes patients, the complications brought on by lockdown restrictions, and the latest recommendations for preventing and managing COVID-19 in diabetes patients. See below for key takeaways and perspectives from this enlightening pair of lectures.

• Diabetes is associated with severe COVID-19 outcomes as a result of direct consequences of the disease process, as well as the increased prevalence of comorbid conditions. Compared to those without diabetes, patients with diabetes are more likely to have elevated levels of inflammation – as well as greater extents of oxidative stress and hypercoagulability –which may compound the body’s innate and adaptive immune responses to viral infection. Further, patients with diabetes are more likely to be older and manage one or multiple comorbid conditions, including obesity, cardiovascular disease, hypertension, chronic kidney disease, non-alcoholic fatty liver disease, and others.

• On a cellular level, Dr. Bornstein reviewed our current understanding for how diabetes influences one’s response to the coronavirus. SARS-CoV-2, the virus causing COVID-19, has been showed to hijack the endocrine pathway involving the ACE2 receptor – this pathway normally serves protective functions in regulating blood pressure, metabolism, and inflammation. With acute hyperglycemia, the expression of ACE2 is upregulated, allowing more and more of the virus to enter the cell in a “vicious cycle reinforcing the disease process.” With chronic hyperglycemia, conversely, the expression of ACE2 is downregulated, decreasing activation of this protective pathway and making one vulnerable to cellular damage and inflammation. The virus can also enter pancreatic beta cells through the DPP-4 receptor, making DPP-4 inhibitors during COVID-19 disease course an attractive therapeutic option.

• To complicate things further, the ACE2 receptor is also expressed in insulin-producing cells of the pancreatic islet. As a consequence, SARS-CoV-2 can directly infect beta cells, induce necroptosis (a type of programmed cell death brought on by viral infection), and blunt the secretion of insulin. In one case study referenced by both Dr. Bornstein and Zimmet, an individual developed new-onset type 1 diabetes shortly following COVID-19 disease course – the direct actions of viral particles on pancreatic beta cells may be to blame.

  • In response to this case study and others of a similar nature, Dr. Zimmet and colleagues recently set up the COVIDIAB Registry, a database “specifically designed to establish the extent and characteristics of new-onset, COVID-19-related diabetes, and to investigate its pathogenesis, management and outcomes. It is also involved in “[collecting] data about presentations with severe metabolic disturbance in pre-existing diabetes (DKA, hyperosmolarity; severe insulin resistance).”

• Lockdown restrictions to slow COVID-19 spread have posed particularly severe challenges for patients with diabetes, as both Drs. Zimmet and Bornstein expanded upon. Spending longer periods of time at home cause changes in one’s eating habits, increase stress, decrease activity, and restrict one’s ability to attend follow-up appointments. All of the aforementioned may contribute to worsening glycemic control, which in turn makes one more susceptible to severe COVID-19. As Dr. Zimmet urged, however, lockdowns are a necessary measure to decrease viral spread and protect a community’s most vulnerable populations. Citing his own Australian state of Victoria as an example, the community has been able to maintain a record of zero new cases and zero lives lost for three weeks to date, as a result of imposing stringent restrictions on normal activities.

• With significant experience on the frontlines of the pandemic, Dr. Bornstein offered his guidance on how to manage diabetes patients who have contracted COVID-19. As expanded upon in his Lancet article from June 2020, Dr. Bornstein expressed that good glycemic control is the best predictor of good outcomes in this vulnerable population. Insulin therapy has thus become the “gold standard” by which to treat COVID-19 patients with diabetes, particularly when combined with continuous glucose monitoring (CGM). Insulin doses often have to be increased following dexamethasone – a steroid treatment routinely given to COVID-19 patients on oxygen – as it leads to hyperglycemia and increased risk of lactic acidosis and diabetic ketoacidosis (DKA). Other routine therapies should be continued, although Dr. Bornstein urged caution about the use of metformin and SGLT-2 inhibitors, which can increase the risk of DKA and lactic acidosis.

2. AZ Symposium Spotlights Interconnection of Heart Failure and Chronic Kidney Disease

A star-studded list of KOLs took to the virtual stage to discuss the role of SGLT-2 inhibitors, and other novel drugs such as Bayer’s non-steroidal MRA finerenone, in HFrEF and CKD. Speakers included cardiologists Dr. Maria Rosa Costanzo (Edward-Elmhurst Health), Dr. Mikhail Kosiborod (Saint Luke’s Health System), and Dr. Muthiah Vaduganathan (Brigham and Women’s Hospital), as well as nephrologist Dr. Katherine Tuttle (Providence Health Care). Broadly, all speakers emphasized that it is an exceptionally exciting time for HFrEF and CKD, fueled by positive data readouts from DAPA-HF, EMPEROR-Reduced, DAPA-CKD, FIDELIO-DKD, and even SOLOIST-WHF for Lexicon’s SGLT-1/2 inhibitor sotagliflozin.

• Dr. Kosiborod focused on the paradigm shift spurred by SGLT-2 inhibitors in HFrEF, highlighting the drug as part of what he calls the “Five Alive” (ACEi/ARB, neprilysin inhibitor, beta blockers, MRAs, and now SGLT-2 inhibitors) of foundational HFrEF treatment. Dr. Kosiborod opened his talk by establishing the bare-bones goals of heart failure treatment: “making our patients live longer, stay out of the hospital, and feel better.” To be sure, the plethora of clinical endpoints used in HFrEF clinical trials can be somewhat overwhelming, but Dr. Kosiborod assured audience members that SGLT-2 inhibitors, primarily dapagliflozin, have posted positive data across all aforementioned categories. Dr. Kosiborod further emphasized that further analyses from DAPA-HF have shown dapagliflozin to be (i) beneficial within days (statistically significant in just 28 days) of treatment; (ii) safe to use in older patients, and even more favorable benefit/ risk balance in patients ≥75 years of age taking dapagliflozin vs. placebo (versus younger patients); and (iii) effective irrespective of baseline HF therapy. Dr. Kosiborod then presented a recent Lancet analysis estimating the lifetime benefit of “comprehensive" therapy (ARNI, beta blocker, MRA and SGLT-2 inhibitors) compared to “traditional” therapy (ACEi/ARB and beta blocker); very impressively, data from the estimate showed that “comprehensive” treatment could extend the lifespan of patients with HFrEF by more than six years. To close, Dr. Kosiborod emphasized that the current sequences of HFrEF treatment (starting with an ACEi/ARB, adding a beta blocker, adding an MRA, etc.) is not based on pathophysiology but rather the timeline of clinical trials. As such, the contemporary approach to HFrEF treatment should embrace new data on SGLT-2 inhibitors and incorporate the drug class earlier in disease progression.

• The ever-engaging Dr. Katherine Tuttle gave a comprehensive overview of the current state of CKD treatment and the potential for SGLT-2 inhibitors, and even GLP-1s, to revolutionize future care. Dr. Tuttle began by emphasizing that although ACE inhibitors and ARBs have been standard of care in CKD for nearly twenty years, both drug classes are woefully underutilized in clinical practice. This grim reality amplified the excitement behind DAPA-CKD’s early stop due to overwhelming efficacy and dapagliflozin’s subsequent Breakthrough Therapy Designation from FDA. As Dr. Tuttle put it, “we’ve never had a Breakthrough Therapy Designation in the field of nephrology before, and CREDENCE and DAPA-CKD were the first clinical trials in our field ever stopped for overwhelming efficacy. This class of agents is truly a win for patients.” While SGLT-2 inhibitors are certainly leading the field, Dr. Tuttle shared that GLP-1s have “striking effects on secondary outcomes [in CVOTs] that harken back to SGLT-2 inhibitors” and “emerging data are all pointing in the same direction.” Using data from the AWARD-7 trial presented at ASN 2020, Dr. Tuttle highlighted the significant reduction in ≥40% eGFR decline/ESKD with Lilly’s dulagutide vs. insulin glargine in patients with CKD. Of course, Novo Nordisk’s ongoing FLOW trial (which Dr. Tuttle noted is 80% enrolled) for semaglutide will help put any ambiguities to rest. To end her talk, Dr. Tuttle highlighted the importance of precision medicine and precision phenotyping in continuing to improve kidney care. While nephrologists “stumbled on SGLT-2 inhibitors and GLP-1s almost by accident,” advances in systems biology have allowed researchers to discover relevant pathways and targets. Currently, Dr. Tuttle is a member of the Kidney Precision Medicine Project, which aims to find disease subgroups to stratify patients and devise individualize treatments.

• To end the symposium, Dr. Vaduganathan called for improved clinical guidelines and diagnostic practices that treat HF and CKD as interrelated conditions, rather than siloed disease states. As shown by recent data from the ARIC registry (n=5,460), multimorbidity is becoming increasingly common in patients with HFrEF, and the line between both conditions is becoming increasingly blurred. On the diagnostic front, Dr. Vaduganathan recommended that cardiologists start to integrate UACR testing in patients with HF, and nephrologists start to test CV biomarkers, such as NTproBNP, in patients with CKD.

Select Question & Answer:

Dr. Yehuda Handelsman: Mikhail, there is a question here about studies on quality of life. I think you may have addressed some of it but do you want to expand?

Dr. Mikhail Kosiborod: I think what we have to keep in mind is when we talk about management in patients with heart failure, it is very important to keep those three pillars of heart failure management in mind. The goals of management are that we want to keep patients living longer. We want to keep them out of the hospital, and we want to improve the quality of life -  because it is a disease that causes a high burden of debilitating symptoms. It impairs physical activity and has a very negative impact on quality of life. Those are key pillars. There are only a few treatments for HFrEF that address all three. In terms of SGLT-2 inhibitors, we do have a treatment that prolongs life and reduces hospitalizations. Now after the DAPA-HF trial, we have a second trial with empagliflozin (EMPEROR-REDUCED) - both showing substantially lower risk of CV death or hospitalization for heart failure. In both the DAPA-HF and EMPEROR-Reduced trials, dapagliflozin and empagliflozin improved the Kansas City Cardiomyopathy Questionnaire scores - which is the gold standard measure of a patient's health status (symptoms, functional status and quality of life). Significantly fewer patients in the DAPA-HF trial showed worsening in their symptoms and significantly more had significant improvements in health status with dapagliflozin versus placebo. Every domain of health status was impacted in a positive way. We have also received just received additional data from the AHA for the effects of empagliflozin on health status in the EMPEROR-REDUCED Trial. It appeared to follow in a similar direction. Thus, we have an intervention that meets the triple goal of keeping patients alive longer, out of the hospital, and feeling better. That is very important to keep in mind because we want to choose therapies that achieve all the key goals of management.  

Dr. Yehuda Handelsman: Anyone else want to say anything? I think that was quite comprehensive. 

Dr. Muthiah Vaduganathan: I thought it was a terrific summary. I will just add two quick points. One is that patient reported outcomes and health related quality of life are rising to the eminence of guidelines, as well as labels. We saw that dapagliflozin was approved by FDA in May of 2020 and was just approved by EMA in Europe for HFrEF. The labeling included, in the package insert, health related QOL data; remarkable for HF; HF hospitalization is a major detriment to health related QOL. We saw last month at AHA, the data from SOLOIST-WHF of patients randomized just after or prior to discharge to sotagliflozin. That therapy was shown to have a remarkable effect on health related QOL, despite being curtailed in terms of enrollment, with an average improvement of KCCQ of 17 to 18 points compared to 13 to 14 points in placebo treated patients; a between group average improvement of four points of KCCQ which is really impressive and supports that there may be magnified effects of SGLT-2 inhibitors on health status in high-risk populations shortly after hospitalization for heart failure.

Dr. Maria Rosa Costanzo: I might add that an important point that we should focus on is that, in contrast to other HF therapies, all three benefits that Mikhail discussed with SGLT-2 inhibitors appear to occur very early. You don't have to wait months to see an improvement in quality of life. You see effects quite early. 

Dr. Yehuda Handelsman: I have a question here both in kidney and HF; now following DAPA-HF and DAPA-CKD, they did not enter here EMPEROR-reduced but could have, can we use SGLT-2 inhibitors in people who do not have diabetes?

Dr. Katherine Tuttle: Yes, I think DAPA-CKD is moving us in that direction. Only a third of the study population had non-diabetic CKD. There have been a number of analyses looking at that group of patients that were presented at the American Nephrology Society Kidney Week. They are going to publish in Lancet Diabetes Endocrinology very shortly. If you look at the non-diabetics, they had comparable benefits to the diabetic population. That lines up very nicely with what we are seeing in the HF trials. The agents appear to help people chronic kidney disease and heart failure irrespective of diabetes status. The issue of guidelines is rapidly evolving. This is not yet in the guidelines, but certainly, the next time a group meets, this will be closely considered. 

Dr. Yehuda Handelsman: It is also important to point out that guidelines follow studies. In the case of dapagliflozin, it is indicated to manage HFpEF. We have known from the prior studies that their impact was independent of glucose and holds true for non-diabetics. Maria, did you want to say something else?

Dr. Maria Rosa Costanzo: I just want to make sure our participants know that in the case of DAPA, this was approved specifically as a drug for HFrEF by the FDA in May of this year. 

Dr. Mikhail Kosiborod: It is approved for HFrEF management in the US, EU, Canada, Japan, and several other places. It is going to transform care not only in the US but elsewhere. Muthiah also mentioned the SOLOIST-WHF trial, which is critically important. There was a significant health status benefit and improvement of KCCQ of over four points on average with sotagliflozin versus placebo in patients with acute heart failure in the hospital or shortly after discharge. It also gave us the first glimpse of the answers to two questions. Can you initiate these agents within a hospital? About half the patients in SOLOIST-WHF were randomized and initiated treatment in a hospital. The answer appears to be yes. There are more trials going on in that regard. Second, what happens to people with HFpEF. I cannot emphasize how important that question is. We’ve never had a disease-modifying treatment for HFpEF before. In the the SOLOIST trial there was no statistical heterogeneity in the benefit of sotagliflozin between reduced and preserved ejection heart failure. This is very promising for the on-going trials with dapagliflozin and empagliflozin in patients with HFpEF. 

Dr. Yehuda Handelsman: There are several questions looking at the whole aspect of guidelines and when they are coming out? One thing I will tell you. There are a couple people who could not participate in this discussion because they are working on the guideline. Muthiah do you want to answer that? 

Dr. Muthiah Vaduganathan: As you mentioned guidelines take time to develop, are peer reviewed, require extensive background systemic reviews. I think we can all make some guesses based on evidence. SGLT2s will be featured prominently in both HF and CKD guidelines. Given that now multiple trials have supported these therapies, they will likely raise the evidence bar of Class 1 indications. The exact timing of guideline publication has not been publicly shared. I will say, in parallel with guideline development, other statements do occur on a quicker timeline. We have seen expert consensus pathways that have been drafted and are in revision which will likely surface very soon. For example, the ACC has an updated Expert Consensus Decision Pathway on HFexpected in the next couple of months supporting SGLT-2 inhibitors as a new standard of care in HF. 

Dr. Yehuda Handelsman: Peter, let me address you. You have done a very good job in differentiating the different types within cardiorenal syndrome and separating them. Now we are addressing both the heart and the kidney. From your perspective, does cardiorenal syndrome fit more than the individual component there or will it always be both kidney and heart?

Peter McCullough: The two organs are inextricably linked - hemodynamically and through so many neurohormonal control mechanisms. I think it is going to be impossible to bear this out. There must be a giant hemodynamic contribution from heart failure to kidney function. What we’ve learned from the trial is that we’ve unlocked some of this with respect to RAAS inhibition and SGLT-2 inhibition. Beyond hemodynamics, SGLT-2 inhibitors must fundamentally change metabolism in cells in such a way whether direct or indirect that they favorably respond or able to survive longer in the setting of kidney disease or HF. For the first time it looks like we are going to be able to extend life and forgo the need of dialysis almost to the point where there will be competing mortality, but the dialysis won’t happen. It is a really remarkable time.

Dr. Maria Rosa Costanzo: I would like to hear Katherine’s opinion. In all the trials, the aspect that caught my attention was the reduction in the rate of decline of eGFR because that is linked to greater end-stage renal disease and cardiovascular mortality. I think that is a fundamental finding of these trials. 

Dr. Katherine Tuttle: I totally agree with you. First off, even the major component of all-cause mortality is cardiovascular in these patients. It is pretty interesting because in DAPA-CKD, they looked at mortality cause by diabetes vs. non-diabetes status. It was recently presented and about to be published. It turns out that the cardiovascular risk is higher in diabetic CKD than non-diabetic CKD, so the risk reduction is greater, but there were also significant reductions in deaths from infection. This was interesting to me from standpoint as the second leading cause of death in this population and in the current pandemic because the number one cause of infection is pneumonia. We do not know how this is working. Maybe as Peter said it best. We have sort of unlocked something that we’re still trying to explain and understand. The mechanisms are extremely important because understanding those will help us target and utilize therapies.

Harkening back to previous comments on goals of therapies. First off is stay alive because that is necessary for anything else to happen. Among the living, fewer rates of severe complications like HF and kidney failure, perhaps even infections. It is a remarkable time. To see a reduction in all-cause mortality in any therapeutic area with any treatment you want to talk about, it is a very high bar. To see 30% reduction in mortalities in heart and kidney failure in a population of people who are already in the clinical trials receiving optimal therapy is really stunning. In nephrology, we have never had trials stop for overwhelming efficacy for CREDENCE or DAPA-CKD. We have had to stop them for safety and futility. DAPA-CKD does not yet have an FDA label for CKD but has a breakthrough status by the FDA. I looked at what other drugs get breakthrough status because we have never had one in kidney disease before. They are almost all oncology - rare tumors or other rare diseases like sickle cell disease. I didn't find any breakthrough therapies in the last two years for chronic diseases. This is a time to celebrate. We still have many challenges and have much research left to be done. We need to find how to use it properly and in the right patients, but what a wonderful time to have this in our toolbox. To have this opportunity is a gift to our patients, but a challenge for us to get it right. In kidney disease, we markedly underutilize even modestly effective therapies. We need to focus on dissemination and implementation to deliver on the promise of living longer and better lives.

3. Sex-Specific Differences in Coronary Artery Calcium, Long-term CV Mortality, and Risk Factors for Development in Heart Failure

Dr. Martha Gulati, Chief of Cardiology at the University of Arizona, opened this session with her research on differences in coronary artery calcium and long-term CV mortality between women and men. Although an estimated 80% of CVD is preventable, there has been an increase in mortality in recent years. The manifestation of cardiovascular disease differs between men and women, with female-specific ischemic heart disease involving positive remodeling, microvascular disease, and endothelial dysfunction, compared to obstructive coronary artery disease in men. Dr. Gulati explained that this suggests sex-specific differences in plaque formation. 

• Women consistently have a higher case fatality rate for CVD, begging the question if atherosclerotic plaque features contribute to more deaths among women. The sex-specific atherosclerotic plaque profile among women includes a smaller plaque burden, less calcified plaque, and less obstructive CAD. Women are also more sensitive to certain risk factors compared to men such as smoking and diabetes. This led to the inclusion of sex-specific risk factors in the 2018 Cholesterol Guidelines of the Atherosclerotic Cardiovascular Disease Risk Calculator (ASCVD).

• Next, Dr. Gulati highlighted a MESA Coronary Artery Calcium study that indicated that a high CAC score was more predictive of CVD in women than men. This result has been confirmed by other studies as well, and Dr. Gulati showed data from the CAC Consortium study, which showed that women were more likely to have higher lesion size and higher plaque density than men even when they had fewer lesions and vessels. CAC predicts CHD, CVD, and all-cause mortality in patients with diabetes, but greater CAC predicts CVD and total mortality more strongly in women.

• In conclusion, women have worse CVD outcomes, partially due to the fact that they are less likely to receive preventive GDMT and are less likely to be referred for risk assessment. The same extent of CAC increased risk more for women than men, are elevated rates of CVD mortality were observed among women with more extensive calcified plaque. Dr. Gulati highlighted the opportunity to further improve the ASCVD risk assessment using this knowledge.

• To follow, Dr. Gina Lundberg from Emory University presented on sex-specific differences in risk factors for the development of heart failure in women. Dr. Lundberg shared both traditional and novel emerging ASCVD risk factors for women, including preterm delivery, hypertensive disorders of pregnancy, and depression. In terms of sex-specific differences in risk factors, emotional stress, vascular stiffness, and systemic inflammation are much greater factors in CVD in women compared to men, and modern-day heart failure manifests in a variety of complicated ways.

• Dr. Lundberg stated that all of these factors point to women having greater endothelial dysfunction, or microvascular coronary dysfunction, and present cardiovascular issues at older ages than men. Men tend to have more macrovascular dysfunction and heart failure with reduced ejection fraction, instead of heart failure with preserved ejection fraction like women. Diabetes has a stronger significance in women for CVD compared to men.

• Maternal mortality is worsening, and 10% of deaths are cardiomyopathy. Dr. Lundberg estimated that up to 68% of these cardiovascular-related pregnancy deaths could be prevented. Part of the difficulty is that many symptoms of cardiovascular such as fatigue and shortness of breath resemble usual pregnancy symptoms.

• In postmenopausal females, Dr. Lundberg discussed Takotsubo Cardiomyopathy, which is stress-induced and can be triggered by strong emotional events. She recommended diagnostic tests, PET, and cardiac MRI. In terms of treatment, she discussed the four pillars of treatment including (i) beta blockers; (ii) SGLT-2 inhibitors; (iii) ARNI drugs; and (iv) mineralocorticoid receptor antagonists. To conclude, Dr. Lundberg referenced all the latest studies on drugs for heart failure as well as diabetes. She urged medical providers to understand sex-specific differences in order to properly tailor cardiovascular treatment for female patients.

Select Question & Answer:

Dr. Matthew Budoff: There’s a question that came in about women and osteoporosis, noting that osteoporosis is more common in women. Is there a relationship with atherosclerosis and osteoporosis in women? Then maybe Martha can touch a little bit on the supplemental question on calcium supplementation and safety in women.

Dr. Martha Gulati: Yes, it’s a good question because there is a causal association between osteoporosis and cardiovascular disease. People with osteoporosis, there’s maybe a four times greater risk of the association with cardiovascular disease. It may be that they share risk factors. Also, osteoporosis and cardiovascular disease also share pathophysiological mechanisms. For example, when someone has osteoporosis, they have more calcium in the bloodstream and more likelihood that the vascular system will get calcified. Additionally, when you have osteoporosis you often get medications. You might get supplementation with calcium, and we know that that also has an association with cardiovascular disease and for coronary artery calcium. So to the question, we think there’s an association, definitely. Do we know if it’s on the pathway? That I cannot answer. What my recommendation is, though, for people with osteoporosis, consider them high risk. Screen them and use coronary artery calcium scanning to assist in ASCVD risk assessment in them because the sooner you know if they are at risk, the more aggressive you can be with your preventative therapies. And I also try to advise them to get as much calcium as possible from diet rather than supplements because of the association with calcium supplementation and a greater risk of cardiovascular disease. Thanks for that great question.

Dr. Matthew Budoff: We have a question for Dr. Lundberg. Why do you think women consistently receive less guideline-directed therapy for heart failure and coronary disease? And also, if you could, I know you touched a lot on the guidelines for heart failure. Are there any drug-specific findings for women where women do better or worse for some of the therapies?

Dr. Gina Lundberg: Yeah, well actually Matt, that was my question to the group! But I am happy to give my comments on it. So for years, in sex-specific studies we’ve seen that women are not put on guideline-appropriate therapy. Whether it’s an acute MI, unstable angina, and now the data I presented today with heart failure. And I don’t think it’s that the doctors are against women, but I think sometimes the women are perceived as being frail or intolerant to the medications. My opinion is sometimes women have lower blood pressure, so they don’t push as hard with the beta blocker or the ace therapy. Put it’s important to have therapy and to give this guideline-directed therapy, so I really wanted to ask Dr. Gulati and Dr. Hodis what their thoughts are on why women receive less guideline-directed therapy if that’s okay.

Dr. Martha Gulati: Sure! I think Gina, that there’s some bias in our medical community about how we perceive a woman being at risk compared to men. There’s also some inertia, meaning if they don’t get started on medications after, say, a myocardial infarction, then usually someone’s not going to start it as outpatient. So we know we have lots of data showing after myocardial infarction women don’t leave with the right kind of medications. And that means they’re not going to get it. Another thing is the close follow-up, the need for cardiac rehabilitation, we know is less, and that’s where they get a lot of their education about why these medications have been prescribed. And another good way of knowing that someone doesn’t have the right education about why they need these medications is after a couple of months when their medication from the hospital runs out, are they still taking it? And many women, more than men, aren’t taking it, because they don’t get the same sort of here’s-what-you-need-to-do after your event.

Dr. Howard Hodis: I think all of that is true, and I think in terms of primary prevention, just the lag time between men and women in terms of when heart disease presents, creates a stake or misperception that women need to be treated as soon as men. So when they do transition mid-life, when the risk does shoot up, very early on at any age (even down into the 30s), women that are post-menopausal have a 2-4 times or perhaps even greater risk than men or women who are premenopausal. So I think that whole premenopausal era really leads to a misperception about women and their future risk, so I think this really does hurt. And when menopause is taken out of the risk stratification, which a lot of us believe is a serious error, I think that this is a great example as to why.

Dr. Matthew Budoff: This is a question to Dr. Gulati about women who have elevated calcium scores. For asymptomatic women whose calcium scores are elevated, do you do a diagnostic test or are there treatment recommendations that you advocate for?

Dr. Martha Gulati: Yes, once you’ve done a coronary artery calcium scan for an asymptomatic woman, I don’t do other diagnostic testing, per se. Hopefully by then I have their lipids and calculated their ASCVD risk and maybe that’s why they got the coronary artery calcification study. At that point, you’re aggressive. And to me, it’s secondary prevention at that standpoint with 450 you really do need – I know there’s a lot of questions about aspirin –but when you have, to me, a coronary calcium above 100, I start using aspirin. And certainly for this particular case with 450, definitely aspirin. They have coronary disease. We aren’t talking primary prevention anymore. So I would get them on the right medications, which would hopefully include a statin and might also include other medications, depending on what their LDL is and what our target goals are. Make sure all of their ASCVD risk factors are addressed, prescribe lifestyle as well, because it isn’t just about medication. This is for someone who is asymptomatic. So I just want to make that clear that they don’t need to go for an additional stress test and you don’t need to send them to the cath lab per se, if you have that information. If they’re symptomatic, that’s a completely different story and a longer discussion than right here and now.

Dr. Matthew Budoff: Thank you very much Martha, that’s great. This is a question to the panel, can you please comment on whether there is any research or known efficacy of PCSK9 inhibitors in women, especially related to morbidity and mortality?

Dr. Gina Lundberg: I’ll take that on. So PCSK9 inhibitors are fairly new, the main ones of course are Repatha and Praluent. But the large studies with them are very strong for reducing morbidity and mortality. They haven’t been great at breaking out the individual data for women, in fact I think the women enrollees are still in the 20-30%, so we need to get more women in them. But they are showing plaque regression that’s much more aggressive than we were able to see with Statin therapy, and the morbidity and mortality outcomes look very good. The women with familial hypercholesterolemia, my FH patients, I really like the PCSK9 inhibitors in them, they’re very well tolerated. So I think we will see that data, we need more people in the trials, we need people to afford the medications with their insurance, and we need sex-specific data and more women enrolled in these trials.

Dr. Tracey Mclaughlin: I have a question for Dr. Lundberg. Regarding the very interesting data you presented on heart failure patterns by sex, that the women are more likely to have plaque and the men are more likely to get reduced ejection fraction, do you see that difference even if you look at diabetic subsets, since diabetics are prone to getting this HFpEF? And then the second question is do you have any comments on drugs, either sex-specific in general, for treating the HFpEF?

Dr. Gina Lundberg: Well I think it’s very important to look at the phenotype and the underlying risk factors in patients with HFpEF. Particularly a female, because there’s a phenotype that has to do with obesity, and that’s where we tend to see more of the diabetes. But then there’s also the little old lady with extreme hypertension, and she’s often very thin. So there tends to be a couple of different phenotypes for this. In the patient with diabetes, the more central obesity, high triglycerides, low HDL, I think exercise, weight loss, restriction of carbs, breads, rice, pasta, all these things, good diabetes control is very, very important. When it comes to medications, we still recommend ace inhibitors or beta blockers as first-line. There’s also HFpEF with people who have uncontrolled AFib, the rate-related, and so at that point it’s very important that you’re getting enough beta blocker to keep the rate controlled. Spironolactone has some very interesting data in HFpEF, and that’s generally a dose of 50 mg twice a day, so that has a lot of good data. And thiazide diuretics as well. So look for the underlying cause, exercise and diet tends to help heart failure a lot, look for sleep apnea in your diabetic overweight patients and control the diabetes.

Dr. Matthew Budoff: I think that you presented some nice data on African-Americans and worsening prognosis, can you expand a little on why you think that is? Is it all just access, or are there other factors on why they specifically do so much worse prognostically with therapies?

Dr. Gina Lundberg: That’s true, and it’s really multifactorial. Access may be part of it, but also they may respond differently to medications. So we know with hypertension, beta blockers don’t tend to be as effective in African-Americans or Blacks. We know that ace and arbs can be beneficial but also amlodipine seems to work really well in them, as well as diuretics. So some of it is possibly a difference in treatment, and again there’s the different phenotypes. If your African-American patient is suffering more from a hypertensive heart failure, then it’s really important to treat that earlier and more aggressively. If it’s more of an ischemia, then you want antianginals as well. So we have to really treat the underlying cause first, and then there may actually be racial differences, yes.

4. Dr. Ralph DeFronzo Highlights “Fatty Kidney Disease” As the Renal Manifestation of Insulin Resistance

Dr. Ralph DeFronzo made the case for “fatty kidney disease” (also called obesity-related glomerulopathy) as the renal manifestation of insulin resistance and metabolic syndrome, and a major driver of diabetes-related kidney disease. The association between obesity and kidney disease is well-known: In a 2016 epidemiological study in Diabetes Care, the risk of kidney disease increased sharply with greater BMI, growing from a 2-fold increased risk with overweight (25-30 kg/m²) to a 3-fold increased risk with class I obesity (30-35 kg/m²) to a 4-fold increased risk with class II obesity (35-40 kg/m²) and finally a 7-fold increased risk with class III obesity (>40 kg/m²). Dr. DeFronzo delved into the mechanism of this phenomenon: He pointed out that just as increased free fatty acid accumulation leads to impaired insulin secretion in the pancreas, decreased glucose uptake in the muscles, and increased hepatic glucose production and eventually NAFLD/NASH in the liver, it also can lead to glomerulopathy of the kidney podocytes. This glomerulopathy in turn leads to a decrease in podocyte density, eventually culminating in albuminuria and kidney cell damage or death. According to Dr. De Fronzo, this “fatty kidney disease” is present in “almost all” of his patients with type 2 diabetes, making it much more common than its much-hyped hepatic counterpart, NAFLD/NASH. Fortunately, there is a pharmacological answer to “fatty kidney disease” in SGLT-2 inhibitors. These agents cause a shift in substrate utilization from glucose to fatty acid oxidation, leading to decreased intracellular levels of toxic lipid metabolites and eventually decreased oxidative and ER stress in kidney podocytes. To this end, dapagliflozin was recently granted Breakthrough Therapy Designation for chronic kidney disease (with or without type 2 diabetes) by the FDA based on the landmark results of the DAPA-CKD trial, which showed a 39% risk reduction for a renal composite endpoint. We expect more SGLT-2 inhibitors will follow in the coming months and years.

5. Dr. Geltrude Mingrone on Obesity and Metabolic Surgery During COVID-19

In the last talk of the Lancet Diabetes & Endocrinology and WCIRDC joint session, Dr. Geltrude Mingrone (Catholic University of the Sacred Heart, Italy and Kings College, England) presented on obesity as a risk factor for severe COVID infections and the safety of metabolic surgery during the pandemic. Dr. Mingrone found an overall consensus that obesity on its own is not a risk factor for severe illness or mortality from COVID-19. The studies found that the percentage of people with obesity who were hospitalized with COVID-19 was in line with the percentage of the population that has obesity. One study in New York reported that 43% of patients on ventilators were obese, which correlates with the prevalence of obesity of 42 or 43% in adults over the age of 60. In another study of 10,000 patients in New York City, the only significant predictor of hospitalization, mechanical ventilation, and death from COVID-19 relating to BMI was for patients with a BMI under 18.5, which suggests malnutrition. However, Dr. Mingrone found that when obesity is paired with comorbidities, such as type 2 diabetes, the risk of severe infection and death due to COVID-19 significantly increases.

• In response to the pandemic, the UK implemented a “Shielding Programme” to protect people who are vulnerable to severe COVID-19 infections. This includes people who are obese or overweight. Dr. Mingrone, however, highlighted the potential dangers of the program for people who are obese but do not have comorbidities. Remaining in lockdown for long periods of time reduces physical activity and can increase food consumption, leading to weight gains and increased risks later on. With this in mind, Dr. Mingrone recommended intensified lifestyle modifications for people with obesity and comorbidities such as diabetes. She also suggested that health care professionals consider prescribing drugs to reduce body weight, such as GLP-1s and SGLT-2 inhibitors. During Q&A, Dr. Mingrone mentioned that a beneficial intervention during the pandemic would be government support to help people afford anti-obesity drugs.

• Finally, Dr. Mingrone discussed metabolic surgery during the COVID-19 pandemic. Dr. Mingrone weighed the risks of disease progression from delayed operations with the risks of contracting COVID-19 and developing a severe infections and complications. Metabolic surgery is known to reduce mortality and microvascular complications. However, metabolic surgeries often keep patients in the hospital overnight, increasing potential exposure for patients and potentially occupying beds needed by COVID-19 patients.

• Dr. Mingrone outlined a prioritization of patients for metabolic surgery. Urgent access, or surgery within 30 days, should be given to people in unstable clinical conditions with severe symptoms of obesity. Expedited access, within 90 days, should be for those at risk of deterioration or for those who need to lose weight to access other surgeries. Finally, standard access, over 90 days, should be for those who are more stable and for whom delaying is unlikely to decrease effectiveness of surgery.

--by Joseph Bell, Ida Claude, Reshma Rajasingh, Rosalind Lucier, Abigail Dove, Rhea Teng, and Kelly Close