Gregory M. Weiss, M.D.

It has been nearly 30 years since the last consensus guidelines were published by the bariatric or weight loss surgery community back in 1991. While the original guidelines were heralded as a breakthrough in weight reduction therapy, Teresa LaMasters, MD, president of the American Society for Metabolic and Bariatric Surgery states,

It’s time for a change in thinking and in practice for the sake of patients. It is long overdue.

There are some important differences from 1991 to now among them a more inclusive selection criterion. But before we visit the new guidelines let’s go back to 1991 see what brought us here today. While the origins of weight loss surgery can be traced back to the 1950s when the first intestinal bypasses were performed widespread use of the modern iteration of that procedure didn’t see broad acceptance and use until the late 80s and early 1990s. With an emphasis on comorbidities such as diabetes and cardiovascular disease, weight loss surgery came into its own. Initial outcomes showed promise while complications still hindered efforts to reach a larger population of obese patients.

As with most new procedures, bariatric surgery in the early years was reserved for the most extreme cases of obesity and only included patients with body mass indices (BMI) of greater than 40 or greater than 35 if they also had several comorbid obesity-related conditions. The new guidelines suggest including patients with BMI >35 and as low as 30 when metabolic diseases are present.

Another key point in the 2022 update to bariatric guidelines is a long overdue validation of the safety and effectiveness of the collection of procedures. Central to the coming-of-age story here is the collective sentiments that:

“Metabolic and bariatric surgery is currently the most effective evidence-based treatment for obesity across all BMI classes”

“Studies with long-term follow up, published in the decades following the 1991 NIH Consensus Statement, have consistently demonstrated that metabolic and bariatric surgery produces superior weight loss outcomes compared with non-operative treatments.”

With greater than 90% of current weight loss procedures consisting of the modern Roux-en-Y Gastric Bypass and the sleeve gastrectomy, older operations have effectively been replaced with safer and more effective ones.1 While combating obesity itself is a worthwhile endeavor we are learning that weight reduction surgery dramatically changes outcomes related to metabolic diseases including diabetes and cardiovascular disease.

A recent study by scientists at Rutgers looked at cardiovascular outcomes after bariatric surgery in obese patients with nonalcoholic fatty liver diseases (NAFLD).

 They found a striking 50% reduction in cardiovascular events such as heart attacks, chest pain, and stroke after bariatric surgery.

The high prevalence of obesity in the United States coupled with cardiovascular disease remaining the leading cause of death for men and women in this country highlights the importance of this update and what it means for obese patients at risk.

Unfortunately, we are reaching far too few patients with obesity. Even before the inclusion criteria for bariatric surgery was broadened only 1 to 2% of the worlds eligible patient population end up getting weight reduction surgery each year.

 This statistic should give us all pause. That means that the vast majority of patients who may realize significant weight loss and freedom from life-threatening comorbidities are not being reached. The impact of doubling and then tripling the number of qualifying patients who receive weight loss surgery could have a staggering impact on so many diseases as well as real reductions in morbidity and mortality related to obesity.

The ASMBS guidelines serve as a wakeup call to all clinicians from the general practitioner to the general surgeon. We must share the benefits of weight reduction surgery with all our obese patients and have a frank discussion with them about the benefits versus the small risks of proceeding with surgery. While a concerted campaign to identify suitable patients is in order, we must be cautious not to ignore the guidelines. While bariatric surgery is by far the most effective and long-lasting weight reduction method for many, regular encouragement and lifestyle modification must still be the foundation on which we build better outcomes for our obese patient population.

https://asmbs.org/articles/after-30-years-new-guidelines-for-weight-loss-surgery

Elsaid MI, Li Y, Bridges JFP, Brock G, Minacapelli CD, Rustgi VK. Association of Bariatric Surgery With Cardiovascular Outcomes in Adults With Severe Obesity and Nonalcoholic Fatty Liver Disease. 

 2022;5(10):e2235003. doi:10.1001/jamanetworkopen.2022.35003

Articles

Gregory Weiss, MD, provides perspective on how improved safety of these procedures has revolutionized the way clinicians view use of bariatric and metabolic surgeries as a method for inducing weight loss in people with overweight and obesity. 

How Evolving Safety Has Changed the Outlook on Bariatric, Metabolic Surgery, with Gregory Weiss, MD

Diabetes affects close to 40 million Americans with as many as half of those going on to develop nerve damage and painful diabetic neuropathy. Neuropathy can lead to severe disability and dramatic reductions in quality of life. 

Once neuropathy sets in, it is often irreversible due to permanent damage to nerve fibers. Historically it has been difficult to predict which diabetics will develop neuropathy and which will not. In fact, glucose control has been shown to prevent neuropathy only marginally down the road.

Although the determinants of neuropathy in type 2 diabetics remain elusive, emerging evidence suggest that obesity and dyslipidemia may be important risk factors.

 A Danish study demonstrated an association between low high-density lipoprotein (HDL) levels and neuropathy.

 Unfortunately data surrounding lipid biomarkers in neuropathy have been limited by the collection of only basic lipid panels on most patients. However, recent advances in mass spectrometry now allow us to examine a greater array of lipids, now termed the lipidome, from routine bio-samples.

“We have the potential to test for these lipid biomarkers in patients with type 2 diabetes to identify those with the highest risk of developing peripheral neuropathy and facilitate more focused management of those patients,” wrote study investigators, who were led by Eva Feldman, MD, PhD, of the University of Michigan.

Feldman and colleagues found a link between developing neuropathy and a critical metabolic pathway called Beta-oxidation which converts lipids into energy used by the nerves.

 When this pathway is blocked, energy starved nerves become damaged, and neuropathy ensues. Even more exciting, the lipid profiles associated with Beta-oxidation inhibition can be recognized as early as 10 years before neuropathy occurs.

The serum lipidomics signature found in this study may be a key prognostic test in the coming future. The authors found, specifically, that decreased serum medium-chain acylcarnitines and increased free fatty acids were associated with development of peripheral neuropathy ten years later.

 They also found that patients who developed neuropathy also had lower phosphatidylcholines and higher lysophosphatidylcholines when compared to those who did not develop neuropathy. These findings give us specific targets, not only for prognosis, but quite possibly targets for treatment.

“As we learn more about the relationship between serum lipid species and neuropathy, it will open up the possibility of targeted therapeutic treatment, both with drugs and lifestyle interventions,” Feldman and colleagues note.

“Our findings support the concept that unsaturated healthy fats are a better source of energy for nerves that highly saturated fats. We strongly recommend a Mediterranean-type diet to maintain a healthy nervous system,” the team continued.

The authors found some common themes here. Obesity and poor diet in general may lead to both hyperglycemia and altered lipid profiles. Now with these data we see that the type of lipid may be a crucial determinant of outcome. Identifying specific lipid signatures that can be tested for early in the course of diabetes, or even in prediabetes offers clinicians the opportunity for earlier intervention. Perhaps if we are able to encourage better diet and more exercise at first discovery of this lipidomic pattern neuropathy could be avoided altogether.

These findings offer us a chance to look at diabetes, altered lipid metabolism, and nerve damage from a higher altitude. The mainstay of lipid management continues to be HMG-CoA Reductase inhibitors or statins which act through cholesterol pathways which, based on this new data, may not prove effective in preventing neuropathy.

 The authors suggest a need for therapeutics that optimize fatty acid metabolism and enhance mitochondrial Beta oxidation.

This brings new hope for diabetic patients facing the pain and disability of peripheral neuropathy.

Afshinnia, F., Reynolds, E. L., Feldman, E. L., et al. Serum lipidomic determinants of human diabetic neuropathy in type 2 diabetes. Annals of Clinical and Translational Neurology. Volume 9, Issue 9 p. 1392-1404

Andersen ST, Witte DR, Dalsgaard EM, et al. Risk factors for incident diabetic polyneuropathy in a cohort with screen-detected type 2 diabetes followed for 13 years: ADDITION-Denmark. Diabetes Care. 2018;41(5):1068-1075.

In this column, Gregory Weiss, MD, reviews recent data suggesting lipid biomarkers could be used to identify patients at increased risk of developing diabetic neuropathy later in life. 

The Possibility of Using Lipid Biomarkers to Predict Diabetic Neuropathy, with Gregory Weiss, MD

There are many benefits to collecting longitudinal data on as many patients as possible. Many of the most important medical discoveries came about either by accident or as a result of investigations into something completely different. 

Developing new drugs for any condition is a costly and time-consuming process during which countless patients continue to suffer and, in many cases, die. In contrast, when a well-known drug is found to be useful for more than one indication the process may be dramatically accelerated.

Atrial fibrillation (AF) remains the most common cardiac rhythm disturbance in the world. As many as 6 million Americans suffer from AF, a disease that carries a significant burden of morbidity and mortality.

 Although many drugs are available to treat AF no significant pharmacologic advances have been made in over a decade. 

Recently researchers at the Cleveland Clinic, utilizing cutting edge genomics-based technology, have found that many of the gene sequences that the diabetes drug metformin targets overlap significantly with genes known to be dysregulated in AF.

AF has been a very difficult disease to treat for cardiologists. Most current drugs only regulate heart rate while many others produce unpleasant side effects.

“Finding drugs or procedures to treat atrial fibrillation is difficult because of potential serious side effects,” said lead investigator Mina Chung MD, of the Cleveland Clinic, on the difficulty of developing new drugs for AF.

Another senior investigator, Feixiong Cheng, PhD, a researcher at the Genomic Medicine Institute in Cleveland, utilized artificial intelligence technology to identify 30 genes metformin targets in common with AF and an additional 8 direct expression pathways they share.

 This approach to finding repurposing strategies for drugs is called network medicine. This paradigm considers the functional and topological organization of gene products as ‘neighborhoods’, so to speak, within the human protein-protein interactome.

 This novel approach allows researchers like Cheng to compare thousands of drugs based on their gene targets and using computer algorithms determine what drugs overlap and thus may be of use in other medical condition. The benefits of this approach are many.

“We can cut off 10+ years in the drug development pipeline. We already have the information there. We just have to test it in a very computationally efficient way, such as artificial intelligence technology,” Cheng said.

Utilizing this network-based approach, the authors were able to identify metformin as a high-confidence candidate for drug repurposing for AF and further, validate it, using gene expression analysis of drug treatments in human cell lines and large-scale pharmacoepidemiologics analysis.

 These are big new words with big implications. While these data were generated by complex mathematic algorithms the associations are grounded in known biochemical mechanisms. Metformin targets a gene sequence that regulates the metabolic stress response reducing oxidative stress and mitochondrial dysfunction which may protect cardiomyocytes from apoptosis under stress.

 In addition to having a protective effect on heart cells, metformin affects gene sequences known for suppressing the renin-aldosterone-angiotensin system further reducing oxidative stress and inflammatory markers that are ubiquitous in patients with AF.

While this approach may be alien to the average clinician and even the traditional bench scientist it is clear that data analytics machine-based research is not only contributing to our field but also here to stay. The next step should be an observational study looking at patients taking metformin for diabetes or pre-diabetes and the prevalence of AF in this population. If an association is found clinically then prospective trials can begin. The authors have shown that new directions can be found without enrolling patients or wasting time pursuing an avenue that leads to a dead end. In essence, network medicine allows researchers to skip a step and go right to investigations with the greatest likelihood of uncovering novel treatments. This is an exciting prospect for clinicians and patients that suffer from AF and so many other conditions.

Lal, J. C., Mao, C., Zhou, Y. et al. Transcriptomics-based network medicine approach identifies metformin as a repurposable drug for atrial fibrillation. Cell Reports Medicine 3, 100749, October 18, 2022

In this column, Gregory Weiss, MD, provides perspective on a recent study providing evidence in support of metformin as a potential therapeutic option for treatment of atrial fibrillation. 

Metformin Pulling Double Duty as Emerging Therapy in AFib, with Gregory Weiss, MD

Obesity continues to be a significant burden leading to a host of comorbid conditions including cardiovascular disease, diabetes, and even cancer. Evidence suggests that obesity puts patients at twice the risk for certain types of cancer and makes them 3.5 times more likely to die from those cancers when compared to obese patients who have undergone bariatric surgery.

Bariatric surgery also known as weight reduction surgery, has been shown in the past to reduce the risk for certain types of cancer. What was not known was the extent weight reduction surgery might mitigate that cancer risk. In an abstract presented at this year’s annual meeting of the American Society for Metabolic and Bariatric Surgery (ASBMS), Jared Miller, MD, and colleagues presented the results of their retrospective cohort study comparing cancer risk in bariatric patients to obese patients not receiving weight reduction surgery.

In total the authors looked at 2,121 obese patients undergoing weight reduction surgery comparing them to 5,528 non-surgical patients with body mass indices (BMI) greater than 30kg/m2.

 The results immediately revealed a significantly lower risk of a new cancer diagnosis in the surgical weight reduction group when compared to non-surgical matched control patients.

The likelihood of a new cancer diagnosis in the weight reduction surgery group was 5.3% compared to 13.4% in the control group.

“The benefits of cancer risk reduction through weight-loss surgery cannot be ignored and should be a consideration for patients with obesity and at high risk for cancer,” said Miller.

Unfortunately, obesity is a problem that is not going away. While obesity is most often related to diabetes and cardiovascular disease, the Centers for Disease Control and Prevention (CDC) estimate that nearly three-quarters of a million obesity-related cancers are diagnosed each year in the United States.

 The authors believe that obesity-related cancers are not only increasing but may be significantly reduced through the use of widespread bariatric surgery. This is a sentiment echoed by the American Society of Clinical Oncology which, in their position statement on cancer and obesity, points out that obesity is a major risk factor for cancer and is associated with worse outcomes after cancer diagnosis.

Although not free from risk, bariatric surgery has been shown produce meaningful and durable weight loss which is associated with resolution or reductions in severity of comorbid diabetes, cardiovascular disease, and hypertension. The ASMBS estimates that over a quarter of a million bariatric surgeries were performed in the United States in 2019. Unfortunately, less than 1% of obese Americans eligible for weight reduction surgery end up receiving it. This dramatic underutilization of this proven procedure is an important target for progress.

Cancer reduction is just the latest headline where bariatric surgery is concerned.

“Weight-loss surgery has proven to be the most effective long-term treatment for obesity and now it’s increasingly being looked upon as a preventative treatment, not only for cancer, but heart disease, stroke and type 2 diabetes too,” said Shanu Kothari, MD, the president of the ASMBS.

This statement underscores the importance of this study. There may be reluctance to considering any type of surgery a preventative measure. This may be in part responsible for the vast numbers of obese Americans not undergoing bariatric surgery. Reluctance should be met with outreach and education. Obesity is broadly associated with stigma. By adding cancer prevention to the reasons for considering weight reduction surgery we as clinicians have another card to play with patients who may be on the fence about the procedure.

The ASMBS is committed to educating patients and healthcare professionals about the benefits of bariatric surgery. This important task is exemplified by this abstract. By clarifying and quantifying the link between cancer and obesity the authors lend importance to the effort to educate patients struggling with weight management. Hope is just as important as research. The former is made possible by the latter.

https://guidebook.com/g/#/guides/am22/lists/1003821/items/14737925

Centers for Disease Control and Prevention. (2015) The Health Effects of Overweight and Obesity. Accessed from: https://www.cdc.gov/healthyweight/effects/index.html

https://ascopubs.org/doi/full/10.1200/JCO.2014.58.4680

Dr. Gregory Weiss provides perspective on data from the American Society for Metabolic and Bariatric Surgery 2022 Annual meeting suggesting patients who underwent bariatric surgery reduced their risk of cancer later in life. 

Undergoing Bariatric Surgery Could Lower Cancer Risk in Patients with Obesity

Diabetes remains one of the most significant health problems in the world. Substantial effort has been made to catch diabetes early and adhere to evidence-based practice in an effort to decrease the incidence of the disease and prevent a myriad of diabetes-related complications. Despite our best efforts as clinicians, the incidence of diabetes in the United States of America has not declined since 2000.

A prediabetic state has been recognized by the Centers for Disease Control and Prevention largely in an effort to intervene before clinical type 2 diabetes has developed. The goal of early recognition of those at risk for type 2 diabetes is to promote a healthy lifestyle through diet, exercise, and weight loss in the hopes of preventing or delaying clinical diabetes and the cardiovascular consequences of elevated blood glucose levels.

Eva Tseng, MD, MPH, assistant professor of medicine at Johns Hopkins, and colleagues recognized the disconnect between prediabetes screening by primary care providers and referrals to nutritionists and endocrinology specialists. As such, Tseng sought to examine the clinical care of prediabetic patients by primary care providers while determining what patient factors influence that care.

 The authors further hoped to understand why the rates of clinical type 2 diabetes have not gone down. Their results were published in the March 2nd edition of the Journal of General Internal Medicine.

The authors examined a large cohort of patients who met laboratory criteria for prediabetes defined as a Hemoglobin A1C between 5.7% and 6.4%.

 Tseng was surprised to find that only 13% of visits to primary care providers in this cohort were coded with prediabetes as a diagnosis.

 Only two-thirds of these patients were ordered follow-up glycemic testing.

 Only 1% of prediabetic patients were referred to a nutritionist and 5.4% started on metformin as treatment.2 Over the twelve months following entry into the cohort, 6% of subjects progressed to type 2 diabetes.

A disconnect clearly exists between initial laboratory studies and interventions that may in many cases be lifesaving in the long term.

“Our results show that we have considerable room to improve in the identification and care of people with prediabetes within our health system and likely in many other places across the United States,” Tseng noted. 

One sliver of good news is that, even though few prediabetic patients were coded as such, the ones that were and received referrals, saw a nutritionist and were prescribed metformin the twelve months after entering the cohort.

 While higher risk patients like those with high body mass indices, and higher glucose levels were more likely to be recognized and referred, they were also more likely to progress to type 2 diabetes in the subsequent year.2

Tseng believes that these results present an opportunity for more aggressive recognition of prediabetes and prompt intervention.

 Patients should be armed with information that may change the course of their health dramatically. This can only occur when prediabetes is recognized, and patients are informed of the basic steps they can take to prevent progression to type 2 diabetes. While medical interventions like metformin therapy can slow the progression to clinical diabetes, patients can do a lot on their own with the right guidance. Even low levels of exercise and small changes in diet can help slow or prevent worsening blood glucose levels and insulin resistance.

While these data are frustrating to clinicians and patients alike, they offer an opportunity to change. Complacency is the antithesis of progress. We cannot afford to be complacent where diabetes is concerned. The cardiovascular sequelae, loss of productivity, reduced quality of life, and costs associated with continued inaction are unacceptable.

The responsibility rests on us all but primary care providers, in particular, must recognize prediabetes, diagnose it, and make the appropriate referrals promptly. If appropriate, metformin should be started and regular laboratory screenings for blood glucose and HgbA1C performed. Those at higher risk should be followed closely and treated aggressively lest they progress to type 2 diabetes more quickly. With vigilance and persistence, we as clinicians can change the trajectory of our prediabetic patients and really make a difference in their lives.

Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2020. Atlanta, GA: Centers for Disease Control and Prevention; 2020.

Tseng, E., MD MPH, Durkin, N., BS, Clark, J. M., MD MPH, et al. Clinical care among individuals with prediabetes in primary care: a retrospective cohort study. 

 (2022). https://doi.org/10.1007/s11606-022-07412-9

Dr. Gregory Weiss discusses prediabetes screening in the US as a method help quell the growing diabetes epidemic in younger populations.

Prediabetes: It’s Never Too Early to Connect the Dots, with Gregory Weiss, MD

Hypertension is one of the most common conditions in the world and is a significant risk factor for kidney disease, stroke, and cardiovascular disease. The primary pathophysiological feature seen with prolonged hypertension is a thickening of arterial walls which, over time, can lead to organ damage. 

Maria Luisa Sequeira-Lopez MD, a physician at the University of Virginia, has uncovered a peculiar association between the pathophysiology of hypertension and the long-term use of a ubiquitous class of blood pressure medications.

A primary target in the management of hypertension is the renin-angiotensin-aldosterone system (RAA). The RAA is primarily responsible for maintaining an adequate blood pressure such that organs are perfused and the organism in question is able to survive and function. The pathology of hypertension is linked to an overactive RAA system. As such angiotensin-converting-enzyme inhibitors (ACEi) were developed as a treatment for hypertension. These drugs prevent the conversion of angiotensin to its vasoconstricting form, angiotensin II. The peculiarity Sequeira-Lopez and colleagues found was that long-term use of ACEi’s lead to the same arteriolar thickening and organ dysfunction, in a mouse model and in humans, that long-term hypertension itself produced.

Sequeira-Lopez looked at mice with an ablated renin gene. What they found was a progressive thickening of the afferent arterioles and interlobular arteries in the mouse kidneys.

 Stranger still, the arteriolar thickening was due to an increase in renin cells within the walls.

 This same phenomenon was seen in human kidneys following extended inhibition of the RAA system.

 At closer examination it was found that the invasive renin cells were not the classic endocrine cells but of a matrix-secretory type that is pathological to kidney arterioles.1 In both cases, human inhibition of the RAA system or renin knock-out mice, invasion of the kidney arteriole by pathological renin cells led to reduced blood flow and ischemia.

These findings are both interesting from a basic science perspective and troubling from a clinical viewpoint. Drugs targeting the RAA system are the mainstay of many hypertension treatment regimens. In fact, ACEi’s and angiotensin receptor blockers (ARBs) are often employed to protect the kidneys in diabetic patients with and without hypertension. Not only are these drugs being used by millions of patients worldwide, they have also been shown to reduce the risk of developing major cardiovascular events including heart attacks, strokes, and death.

These conflicting findings present a bit of a dilemma. For Sequeira-Lopez’s part she does not advocate for discontinuation of ACEi or ARB treatments at this time. She does however call for prospective, randomized, controlled investigations aimed at defining the real-life implications of her findings. Ultimately, we as clinicians measure the effectiveness of our treatments based on outcomes. Even though these data indicate that drugs targeting the RAA system cause thickening of renal arterioles the fact that these drugs are associated with better survival and in most cases increased quality of life should be the driving factor. The role of basic science research is to determine what the figuratively microscopic factors are that produce our macroscopic clinical picture. Now that these authors have uncovered a potential problem with a trusted and proven hypertension treatment it will be up to others to examine the clinical implications in the short and long term.

With over a billion people suffering from hypertension worldwide this discovery warrants a closer look. How can it be that the very treatment produces the same pathological sequelae as the disease itself? It is not uncommon for a study to raise more questions than answers. This is the basis of discovery. By building on good science, we find answers and start asking more questions. With a fresh look at an old treatment, we see here that the book isn’t closed on RAA inhibition.

Watanabe, H., Martini, A. G., Sequeira-Lopez, M. L. S., et al. Inhibition of the renin-angiotensin system causes concentric hypertrophy of renal arterioles in mice and humans. 

Dusing R. Mega clinical trials which have shaped the RAS intervention clinical practice. 

Dr. Gregory Weiss provides perspective on recent data detailing the potential for kidney damage as a result of long-term inhibition of the renin-angiotensin system. 