The learning continues at CMHC! On day #3, we attended outstanding presentations by Drs. Anne Peters (on the promise of semaglutide for even better glucose-lowering than what we can achieve now) and Wendy Lane (on how CV risk mitigation should be the central goal of any type 2 diabetes treatment plan). This is always an intimate meeting, with speakers willing to debate and share their clinical opinions. Indeed, we picked up on great commentary in support of TZD pioglitazone for NASH (from Drs. Jay Skyler and Robert Eckel), we heard Dr. Peters’ message that she doesn’t consider Jardiance (empagliflozin) to be a glucose-lowering drug, and we were inspired by Ms. Janet de Jesus’ attack on sugar-sweetened beverages (this is an important public health movement). The day #3 agenda featured plenty of basic science, and for those of you most interested in this early-stage research on diabetes/obesity therapies of the future, we recommend highlights no. 5-8.
In case you missed it, our top 10 highlights from CMHC days #1-2 are posted here, and our full conference preview is here – we’ll have one more installment of highlights from this meeting after the weekend.
Top Eight Highlights
1. Tasked with updating the CMHC community on therapies for glucose-lowering, Dr. Anne Peters drew from CVOT data and her own clinical experience to distinguish what works from what doesn’t. She put Novo Nordisk’s GLP-1 agonist candidate semaglutide on one end of the spectrum (“an amazing drug in terms of A1c reduction”), and put Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin) on the other (“showed the least impressive glucose-lowering in these trials”). She also left us with a moving quote on access: “I like to think we’ve conquered the world. Retinopathy should be a thing of the past, and it is, in my Beverly Hills clinic. But I take care of patients in East Los Angeles every other day, where people struggle with access to healthcare, and do go blind all the time from diabetes complications. And it breaks my heart, because I know I can prevent this.”
2. Dr. Wendy Lane described historical type 2 diabetes treatment algorithms as a single bullseye targeting A1c – not even glucose profile or glycemic variation, but just an average. Fast forward to now, and her slide changed to display a multi-ring target, with CV risk reduction at the center.
3. In an interactive discussion of complex cardiometabolic patient cases, Drs. Jay Skyler and Robert Eckel endorsed TZD pioglitazone for NASH (but emphasized that this is not yet an FDA-approved indication for the generic drug).
4. NIH nutritionist Ms. Janet de Jesus came down hard on added sugar, and advised clinicians that one of the most important questions they can ask patients is “what are you drinking?”
5. Friday afternoon at CMHC was dedicated to diabetes management, and there was no better way to kick things off than with an expert lecture on insulin resistance by Dr. Ronald Kahn. He emphasized its role at the center of diabetes pathophysiology, obesity, central obesity, hypertension, dyslipidemia, hepatic steatosis, increased cancer risk, Alzheimer’s disease, accelerated atherosclerosis, and reproductive dysfunction… it was quite a list, and we were particularly intrigued by his discussion of insulin resistance in the brain/Alzheimer’s Disease.
6. Dr. Stanley Hazen delivered a compelling keynote address on the role of the microbiome in cardiometabolic disease, leading the audience through a deep dive into the potential role of the microbiome metabolite trimethylamine N-oxide (TMAO) in engendering risk for thrombosis, particularly MI and stroke. He asserted that soon we will begin to conceptualize the microbiome as a fully-fledged endocrine organ in its own right.
7. Dr. Barbara Kahn delivered an outstanding presentation connecting insulin resistance to both diabetes and obesity, focusing especially on the role of white adipose tissue is regulating whole body metabolism and inflammation.
8. In a special interest session (we sure learned a lot), Harvard and Brigham and Women's Hospital’s Dr. Frank Scheer discussed his research connecting circadian rhythms to metabolic health, including diabetes, prediabetes, obesity, and CV disease.
Top Eight Highlights
1. Dr. Peters Praises Semaglutide for Glycemic Efficacy, Doesn’t Consider Jardiance to be a Glucose-Lowering Drug
Tasked with updating the CMHC community on therapies for glucose-lowering, Dr. Anne Peters drew from CVOT data and her own clinical experience to distinguish what works from what doesn’t. She put Novo Nordisk’s GLP-1 agonist candidate semaglutide on one end of the spectrum (“an amazing drug in terms of A1c reduction”), and put Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin) on the other (“showed the least impressive glucose-lowering in these trials”). In reviewing SUSTAIN 6 results, Dr. Peters highlighted the marked drop in A1c from a baseline 8.7% to near 7% in the 1.0 mg semaglutide arm (for comparison, patients on 0.5 mg semaglutide experienced a mean A1c decline from 8.7% to 7.6%, while those on placebo experienced a mean decline to 8.3%). She added that it’s also impressive how this glucose-lowering effect was sustained throughout the two-year trial, with patients in the high-dose semaglutide arm maintaining A1cs between 7% and 7.5%, though she remarked that 104 weeks is relatively short for a CVOT. Dr. Peters established that this is a larger margin of A1c-lowering than has been seen in other large outcomes trials for a single therapy. Indeed, at ESC 2017, Dr. Esteban Jodar explained the larger A1c treatment difference in SUSTAIN 6 vs. other CVOTs by positioning semaglutide as a very potent molecule – this seems to be the consensus among thought leaders, as we approach the FDA Advisory Committee date (October 18) for this once-weekly product’s approval. Turning to EMPA-REG OUTCOME for empagliflozin, Dr. Peters showed a reduction in A1c with the SGLT-2 inhibitor that returns back to ~8% after 206 weeks (re-approaching baseline). Candidly, she stated that she doesn’t consider Jardiance to be a glucose-lowering drug. “I don’t see that much glucose-lowering in my patients, though I do see improvements in other CV risk factors.” While she didn’t call out J&J’s Invokana (canagliflozin) in this talk, we heard from Dr. Peters shortly after the CANVAS results presentation at ADA that she’s seen more success in her clinic with canagliflozin vs. empagliflozin, in terms of A1c reductions and weight loss. That said, A1c data was similar in CANVAS compared to EMPA-REG OUTCOME, with a large initial drop that was attenuated over time. Importantly, Dr. Peters did not undersell the profound CV benefits associated with Jardiance. She didn’t delve into cardioprotective effects at all, because the focus of these remarks was on treatments for glycemia, and to that end she underscored the need for combination approaches to achieve long-term glycemic control (given the rebound in A1c from empagliflozin therapy).
- Dr. Peters anchored her message on the importance of good glycemic control by describing how higher A1c increases risk for microvascular complications, which in turn deteriorate a person’s quality of life. “I like to think we’ve conquered the world. Retinopathy should be a thing of the past, and it is, in my Beverly Hills clinic. But I take care of patients in East Los Angeles every other day, where people struggle with access to healthcare, and do go blind all the time from diabetes complications. And it breaks my heart, because I know I can prevent this.”
2. Dr. Lane: Controlling CV Risk Should be at the “Heart” of Diabetes Management
Dr. Wendy Lane described historical type 2 diabetes treatment algorithms as a single bullseye targeting A1c – not even glucose profile or glycemic variation, but just an average. Fast forward to now, and her slide changed to display a multi-ring target, with CV risk reduction at the center. What’s powered this paradigm shift, she explained, is the emergence of positive CVOT data supporting the cardioprotective effects of approved diabetes drugs. Groundbreaking EMPA-REG OUTCOME results led the ADA to recommend empagliflozin (Lilly/BI’s SGLT-2 inhibitor Jardiance) for patients with type 2 diabetes and high CV risk in its 2017 Standards of Care, and the FDA approved a new CV indication for the product label. Similarly, LEADER data on Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) led to an ADA endorsement in its Standards of Care and an FDA-approved label update to reflect risk reduction for major adverse CV events. Dr. Lane described this more nuanced approach to diabetes care as a clear improvement. She encouraged HCPs in the room to aim for the heart of the target – “no pun intended,” she said. Given that CV disease remains the leading cause of death for people with type 2 diabetes, and given the enormous impact of CV events on quality of life and overall healthcare costs (due to hospitalizations, productivity loss, need for additional concomitant medications, etc.), we agree that this multi-ring target makes much more sense than the old way of doing things. With educational sessions like this, we’re glad to see HCPs being called-to-action around the paradigm shift in diabetes care, which is now also cardiology care. This symposium was jointly sponsored by Novo Nordisk and Lilly/BI, and we hope that manufacturers of cardioprotective diabetes drugs can work collaboratively going forward to increase knowledge at the intersection of type 2 diabetes and CV disease.
- What about the other rings surrounding CV risk reduction at the heart of the target? Dr. Lane’s slides listed these as glycemic variability, A1c, weight, and hypoglycemia, and she reiterated that the glycemic and non-glycemic outcomes goals are equally important. She praised the most recent iteration of AACE guidelines for its 14 principles that closely match these priorities in diabetes care (and that push the outcomes beyond A1c movement forward). Specifically, Dr. Lane highlighted principle #5, the idea that choice of therapy should be individualized based on a patient’s medical history, characteristics, formulary restrictions (cost), and personal preference. She underscored principle #6, the idea that minimizing hypoglycemia should be a priority, and urged providers to use more advanced agents in place of sulfonylureas, which confer a known hypoglycemia risk (yes, this needs to continue to be said). She underlined principle #7, the idea that therapy needs to help patients with weight loss, or at least weight maintenance. And lastly, Dr. Lane called attention to principle #11, the idea that comprehensive diabetes management needs to control lipids, blood pressure, and related comorbidities. Circling back to her main point, she emphasized that “it ain’t just about glucose anymore,” because best practice diabetes care should really focus on health outcomes, not A1c.
3. Pioglitazone for NASH?
In an interactive discussion of complex cardiometabolic patient cases, Drs. Jay Skyler and Robert Eckel endorsed TZD pioglitazone for NASH (but emphasized that this is not yet an FDA-approved indication for the generic drug). Reducing liver fat is a critical aspect to cardiometabolic disease management, according to Dr. Skyler. The cases presented involved some combination of type 2 diabetes, obesity, NASH, hypertension, dyslipidemia, etc., and liver fat was repeatedly mentioned as a core piece of cardiometabolic health. Here, pioglitazone could help. Dr. Eckel alluded to some of the safety concerns surrounding the TZD therapy class, which explain the drop-off in prescriptions seen in recent years, but underscored that most of this worry stemmed from rosiglitazone rather than pioglitazone. Low-dose pioglitazone (15 mg, no more than 30 mg) is less convincingly linked to bone disease, Dr. Eckel stated, and could prove incredibly beneficial in patients with more insulin resistance and NAFLD/NASH. Plus, he reminded the room that this agent is generic now, and therefore lower in cost. “We have some 30 treatments in development for NASH,” Dr. Skyler stated (see our competitive landscape for the list), “and none are approved yet, but we can turn to pioglitazone. I do.” NASH is an area of enormously high unmet need, and we hope to hear more about potential applications of pioglitazone for this condition at the European NASH summit next week.
4. Experts Discuss Diet and Behavior Change Strategies for Cardiometabolic Health
A morning symposium on dietary recommendations to support cardiometabolic health featured wide-ranging commentary from experts on micronutrients, macronutrients, and the psychology of behavior change. On micronutrients, Wake Forest’s Dr. Jamy Ard discussed the emerging role of potassium in blood pressure management. Although there is not yet enough data on potassium to support an official dietary recommendation to increase potassium intake as a blood pressure control strategy, preliminary evidence suggests that this micronutrient can counteract the hypertension-inducing effects of excess sodium. A diet enriched with potassium could therefore be very strategic in the present food environment, where sodium is “baked into the food supply” at high levels. Dr. Ard noted that high-potassium foods (essentially all fruits and vegetables) have the added benefit of being low in sodium themselves. He added that potassium-rich food is an easier proposition for patients than consciously subtracting foods high in sodium.
- On macronutrients, NIH nutritionist Ms. Janet de Jesus came down hard on added sugar, and advised clinicians that one of the most important questions they can ask patients is “what are you drinking?” As much as half of all added sugar comes from beverages, and reducing consumption of soda and sugar sweetened beverages is her first recommendation for people who come to her for weight loss advice.
- On behavior change, Dr. John Foreyt, director of the Behavioral Medicine Research Center at Baylor College of Medicine, emphasized that patients are most successful at losing weight when their goals are framed in terms of functional aspirations rather than numbers on a scale. As an example, he suggested “I want to be able to play with my grandchildren without getting tired” instead of “I want to lose 10 pounds”. He also wisely pointed out that a patient’s support system, stress level, and psychological factors are as important to assess in developing a treatment plan as their BMI, A1c, and cholesterol levels.
- All three speakers endorsed a “small steps” approach toward incrementally making healthy lifestyle changes – a philosophy that Dr. Christie Ballantyne challenged during Q&A, noting that major progress requires major behavioral improvements: “If you smoke three packs a day and go down to two, that’s progress, but we really want you to stop smoking. And if you get 3,000 steps per day, 3,500 steps isn’t much better – we need you at 10,000.” We agree with the implication that incremental change will only be effective if there are ways of ensuring that it builds into substantial, clinically-meaningful change. Although there is still much more to be learned about precisely which behaviors are the most impactful to change, this pales in comparison to the issue of how to actually impart new behaviors.
5. Dr. Ronald Kahn Presents the Many Faces of Insulin Resistance
Friday afternoon at CMHC was dedicated to diabetes management, and there was no better way to kick things off than with an expert lecture on insulin resistance by Dr. Ronald Kahn. He emphasized its role at the center of diabetes pathophysiology, obesity, central obesity, hypertension, dyslipidemia, hepatic steatosis, increased cancer risk, Alzheimer’s disease, accelerated atherosclerosis, and reproductive dysfunction… it was quite a list. Dr. Kahn outlined how insulin resistance can be characterized in one of two ways: (i) by decreased receptor sensitivity, which usually results from a defect in the protein and demands higher insulin concentration for a particular level of response, or (ii) by decreased responsiveness of the receptor, which usually results from a defect later on in the protein pathway. That insulin resistance can be subdivided like this is telling in itself, implying that we need more than one-size-fits-all approaches to treatment. Moreover, it’s fitting that the condition underlying a host of cardiometabolic disease states is nuanced in itself (making personalized medicine all the more important). Zooming in to the cellular level, Dr. Kahn described the mechanistic basis for insulin resistance: Upon reception of insulin, the insulin/IGF-1 receptors auto-phosphorylate, then phosphorylate insulin receptor substrates (IRS) that combine to drive forward either the PI 3-Kinase or MAP Kinase pathways. Downstream, the PI3K pathway promotes glucose transport through protein synthesis – in obesity, this pathway is not well-stimulated, and it behaves even worse in diabetes, resulting in insulin resistance. Particularly striking is that even in clinical prediabetes, patients have glucose uptake levels no better than those with fully-fledged type 2 diabetes – the difference being that those in prediabetes can still compensate with hyperinsulinemia. We also appreciated Dr. Kahn’s discussion of insulin resistance in the brain and its link to Alzheimer’s Disease (or, as some call it, “type 3 diabetes”). Compelling evidence in knockout mice demonstrates that insulin signaling in the brain is important for cognitive function, mood, and behavior control. Knocking out the insulin receptor in the hippocampus (memory center) of mice results in learning deficits as well as short- and long-term memory deficits. Moreover, studies are starting to show how resistance manifests in the human brain. Small trials have begun to examine the use of diabetes drugs in Alzheimer’s disease (especially GLP-1 agonists like Novo Nordisk’s liraglutide), underscoring truly extensive impact of metabolic syndrome on the human body.
6. Gut Microbes as a Therapeutic Target in Cardiometabolic Disease? Dr. Hazen Discusses a Role for Microbiome Metabolite TMAO in MI/Stroke Risk
Dr. Stanley Hazen delivered a compelling keynote address on the role of the microbiome in cardiometabolic disease, leading the audience through a deep dive into the potential role of the microbiome metabolite trimethylamine N-oxide (TMAO) in engendering risk for thrombosis, particularly MI and stroke. TMAO is a byproduct of gut microbes breaking down dietary choline, a nutrient found in the lipid phosphatidylcholine (also termed lecithin), which is found in many staples of the Western diet, including meat, high-fat dairy products, and egg yolk. In an initial examination of blood samples from >4,000 patients at the Cleveland Clinic, plasma TMAO levels were found to strongly predict risk for a thrombotic event. More recent meta-analyses looking at >26,000 individuals confirm that plasma or serum levels of TMAO are associated with incident CV morbidity/mortality risk, in both primary and secondary prevention patients. Dr. Hazen discussed animal studies from his own lab, which further underscore the relationship between TMAO and CV disease in a causal rather than correlational manner. In a recent microbial transplantation study, researchers harvested intestinal microbes from an inbred mouse strain that is thrombosis-prone and noted to have high TMAO producing microbes vs. intestinal microbes recovered from a low TMAO producing inbred strain of mice, and then transplanted these microbes into germ-free mice as recipients. Sure enough, the mice who received the transplant from the high-TMAO producing microbes were more prone to development of thrombosis, whereas the mice who received the transplant from the low-TMAO producing microbes showed reduced platelet reactivity and thrombosis potential during in vivo thrombosis model studies. Such studies thus show that gut microbes, via production of TMAO, impact platelet function and thrombosis potential. Dr. Hazen described how a similar effect was observed in a small in-human study earlier this year, in which just two months of choline supplementation (a 450 mg daily dose, equivalent to 3.5 eggs) in healthy volunteers produced >10-fold increases in plasma TMAO and a corresponding increase in blood platelet aggregation, perhaps foreshadowing greater risk of blood clotting and thrombosis. In terms of the clinical implications of this suggested connection between TMAO and thrombosis, dietary modification to reduce choline consumption is one obvious solution. Dr. Hazen reviewed results of studies showing vegetarians and vegans have lower TMAO than omnivores, and that adherence to a Mediterranean diet is associated with reduction in TMAO levels. He also alluded to a future of “personalized medicine for you and your gut microbes” involving the development of drugs that inhibit the bacterial enzymes responsible for creating TMAO (or any other metabolite for that matter) to reduce thrombosis, and consequently the risk of thrombotic events like MI or stroke. Dr. Hazen left the audience with reassurance that this example is just the tip of the iceberg when it comes to “drugging” the microbiome.
- Additional studies in Dr. Hazen’s lab suggest that the phosphatidylcholine to gut microbe to TMAO pathway has potential implications not only for thrombosis, but also heart failure, atherosclerosis, and CKD, and, of course TMAO is only one of many, many metabolites generated by gut microbes that influences everything from obesity to insulin resistance to blood pressure. Dr. Hazen asserted that soon we will begin to conceptualize the microbiome as a fully-fledged endocrine organ in its own right. The microbiome remains one of the hottest topics in obesity basic science, and we are excited to see this appreciation for the crucial role of the microbiome in health spilling over into cardiometabolic disease more broadly. These are certainly early days, but we feel lucky to have a front row seat to witness these exciting scientific developments, which, as Dr. Hazen pointed out, may very well become the basis of next-generation therapies for metabolic disease.
7. Dr. Kahn Presents New Science on Insulin Resistance and Obesity
Dr. Barbara Kahn delivered an outstanding presentation connecting insulin resistance to both diabetes and obesity, focusing especially on the role of white adipose tissue is regulating whole body metabolism and inflammation. White adipose tissue is a storage depot, but also acts as an endocrine gland, secreting hormones, cytokines and proteins such as retinol binding protein 4 (RBP4). Dr. Kahn explained that RBP4 is made in the liver and in adipose tissue, is secreted, and is metabolized in cells to retinoic acid, which transduces expression of hundreds of genes. RBP4 has been heavily implicated in insulin resistance, as a mediator of adipose inflammation and insulin resistance. As Dr. Kahn pointed out, serum RBP4 is elevated in insulin resistant states in humans, before type 2 diabetes is apparent – the opportunity for prevention here is intriguing. Moreover, therapies that improve insulin sensitivity result in lower serum RBP4 levels, and studies in mouse models have shown that RBP4 is a cause, as well as a marker, of insulin resistance. Continuing on, Dr. Kahn demonstrated that higher RBP4 is correlated with dyslipidemia, hypertension, obesity, high waist:hip ratio, inflammation, and hepatic steatosis in human, underscoring its potential strong influence at the crux of metabolic health in general. Dr. Kahn and her colleagues have shown that RBP4 causes insulin resistance by eliciting white adipose tissue inflammation and this is independent of retinol. She outlined how RBP4 induces the production of inflammatory cytokines (TNFa, IL-6), leading to impaired insulin signaling and higher diabetes risk, and how injection of RBP4-activated antigen-presenting cells into normal mice is sufficient to cause inflammation and insulin resistance, indicating causality. This was a whirlwind of basic science, but Dr. Kahn made clear the possible applications to our understanding of diabetes/obesity development and treatment. Interest in white adipose tissue is certainly growing, and we’re excited for the next wave of findings.
- According to Dr. Kahn, RBP4 is just the tip of the iceberg: A gene set enrichment analysis revealed that fatty acid synthesis is one of the most highly-regulated GLUT4-mediated pathways. Interestingly, adipose-GLUT4 overexpressing mice have obesity but also enhanced glucose tolerance and enhanced fatty acid synthesis, disrupting the usual association between obesity and insulin resistance/glucose intolerance. This is where Carbohydrate Response Element Binding Protein (ChREBP), a transcription factor regulating glycolysis and lipogenesis, comes into play. Adipose ChREBP level is correlated with insulin sensitivity in humans, and ChREBP has been found to be critical for lipogenesis in adipose tissue. Further, Dr. Kahn described how ChREBP reduction in adipocytes, in otherwise normal mice, is sufficient to cause systemic and hepatic insulin resistance, affecting both the liver and muscle.
- Dr. Kahn’s team has identified a novel class of fatty acids, produced through lipogenesis, via lipidomic analysis. These were characterized as branched fatty acid esters of hydroxyl fatty acids (FAHFAs), and were found to be upregulated in the adipose tissue of adipose-GLUT4 overexpressing mice. When looking at these novel lipids in people with insulin resistance, higher serum levels were strongly correlated with higher insulin sensitivity, and levels were reduced in the adipose tissue of insulin-resistant humans. These lipids have also been shown to promote GLP-1 and insulin secretion and to reduce adipose tissue inflammation. This work has exciting applications and potential targets for restoring insulin sensitivity and possibly treating or preventing type 2 diabetes, although further research is needed to characterize the mechanistic role of these novel lipids in inflammation, GLP-1 and insulin secretion, and GLUT4 translocation.
8. Dr. Frank Scheer on Metabolism and the Biological Clock
In a special interest session (we sure learned a lot), Harvard and Brigham and Women's Hospital’s Dr. Frank Scheer discussed his research connecting circadian rhythms to metabolic health, including diabetes, prediabetes, obesity, and CV disease. Dr. Scheer described how many circulating cardiovascular risk factors fluctuate in concentration on a circadian basis, driven by our internal circadian clock. As one example, his lab demonstrated that pro-thrombotic protein PAI-1 accumulates throughout the night and falls throughout the day, peaking in concentration at ~6:30 am and hitting its lowest levels at ~2:30 pm, independent of behavioral and environmental influences (the accompanying Editorial clarified that we’re having “PAI” for breakfast whether we like it or not). Furthermore, given that the regulation of metabolism also takes place on a tight circadian basis, it is perhaps unsurprising that circadian misalignment (as is typical with jetlag, shift work, etc.) has adverse consequences for glycemic control and CV health. Epidemiological studies show a correlation between shift work and the development of obesity, diabetes, and CV disease, and Dr. Scheer’s work corroborates that circadian misalignment is indeed causally related to these cardiometabolic conditions. In one in-laboratory study, individuals (n=10) subjected to circadian misalignment by living on 28-hour ‘days’ in a controlled laboratory setting in dim light conditions for 10 days showed increased mean arterial pressure and increased postprandial blood glucose, with three participants exhibiting a glucose response typical of prediabetes. Interestingly, Dr. Scheer explained that mis-timing between behaviors and circadian factors is not restricted to shift work and jet lag, but to some degree is also observed when eating closely to the intake of melatonin or closely to bedtime. Eating when circulating melatonin concentrations are elevated causes relative impairment of glucose tolerance. These adverse glycemic effects shows large interindividual differences that can be linked to genetic variants of a gene encoding the melatonin 1b receptor (MTNR1B). This risk variant rs10830963 is surprisingly common, present in ~50% of the population. According to a hot-off-the-press 2017 paper by de Luis et al., this particular polymorphism is also associated with lack of improvements in body weight and insulin resistance in response to a dietary intervention that improved these parameters in people without the high-risk genotype. As signaled by the recent announcement of the Nobel Prize in Physiology or Medicine – which was awarded to a group of scientists studying the biological clock – circadian rhythmicity is a fundamental and, until now, under-appreciated aspect of our biology. This fascinating work, though early-stage, adds one additional layer of complexity to our understanding of the multifactorial nature of cardiometabolic disease risk.
-- by Ann Carracher, Abigail Dove, Payal Marathe, and Kelly Close