Katherine Saunders, MD: Let’s start with the big picture. What’s the greatest change you’ve seen in Obesity Medicine over the last 10 years?

Louis Aronne, MD: The biggest change is a change in the attitude of the public about taking medicine to treat obesity. And I think that’s come about because of the development of new, highly effective treatments and their increased use. It’s now clear that obesity can be treated, and doing so brings enormous benefit.

Saunders: How much of this willingness to take medication for obesity do you attribute to the growing recognition of obesity as a disease?

Aronne: I think it took having a treatment to really convince people that obesity is a disease. Before, even though obesity had been declared a disease by numerous organizations, people still didn’t believe it. People didn’t believe that there were medical treatments that would work. However, I also think that if we had the treatments but didn’t have the support of the major medical organizations like the AMA, we wouldn’t be where we are today. I believe it’s really the combination of the two that’s catalyzed this dramatic change in the way people view obesity.

Saunders: You’ve been arguing since the 1980s that obesity is a disease, but it took a long time for the rest of the medical community to come around. And now it seems like we’ve gone to the other extreme, with so many people taking these medicines whether they’re indicated or not.

Aronne: True, but in the future, we may treat people at lower BMIs. I like to use the analogy of blood pressure: maybe the right thing is to treat earlier. If we treat someone with a BMI of 25 and reduce it to 23, they’ll need less medication and they’ll end up with fewer side effects. There are a number of reasons why the treatment paradigm of using medications earlier could be a good thing.

Saunders: What do you think it will take for treating earlier — treating pre-obesity — to become the standard of care?

Aronne: The first step will be outcome studies showing that people live longer if they lose weight. Once we have that data, it will make sense for insurers and employers to cover these treatments. It will make more sense to treat people earlier to prevent them from having heart attacks or strokes or developing diabetes, which are all very expensive. We already know that losing weight makes people much less likely to develop diabetes, and that 15% weight loss can produce diabetes remission in the vast majority of cases. I think these dramatic health benefits will be apparent to insurers and employers.

Saunders: To improve access, we need better insurance coverage, and we also need medications to be less expensive at some point.

Aronne: We really need to make larger, systemic changes to bring down prices and improve coverage. These issues are not specific to anti-obesity medications — all new medicines are expensive when they come out, and most of them don’t have the potential benefit that an anti-obesity medication has. My hope is that the prices will come down, but the system will have to change as part of that effort.

Saunders: Let’s talk about the science of obesity. We’ve learned so much in recent years, but there’s still so much that we don’t know about this complex, chronic, heterogenous, relapsing disease. If you could snap your fingers and magically have the answer to one question, or clarify one aspect that we still don’t understand about the science of obesity, what would it be?

Aronne: One fascinating question relates to the heterogeneity of responses to treatment. You can use the same treatment on a thousand people, and some will lose 30%–40% of their body weight or more, and some won’t lose any weight. What causes that difference? What are the characteristics of someone who loses a lot versus someone who doesn’t? That would be incredibly useful to know.

Saunders: There’s been a great deal of progress in anti-obesity pharmacotherapy in the decade since the AMA’s decision to recognize obesity as a disease. What do you think we’ll see in this area in the next 10 years?

Aronne: I think we’ll see many more compounds affecting many more targets. Right now, we’re focusing on the hormone GLP-1, and now with tirzepatide we have GLP-1 plus GIP, but in the future there will be many potential targets. There is already evidence that the efficacy of some drugs will rival that of bariatric surgery. We already have compounds in the pipeline that will be more effective than the best current medications. We’ll also see oral agents that are as effective as injectables.

Another area of work will involve lean mass preservation. When you lose weight, optimally you lose three-quarters fat and one-quarter lean mass, but there’s evidence that preserving muscle may help in a number of ways. Now, we expect patients to start regaining weight right away when they stop taking a medicine, but if muscle mass is preserved, the weight doesn’t seem to go back up right away.

And finally, I think the model for pharmacotherapy for obesity will eventually be similar to what we see for hypertension. We’ll have a medicine that’s readily available, and you’ll have access to it as soon as your weight goes over a certain threshold, which could be based on weight, BMI, waist size, blood sugar, or other complication. We’ll be treating people with prediabetes and pre-pre-diabetes, which will dramatically reduce the need for diabetes medicines and prevent other health problems that we spend a lot of money on. Just imagine if we could stop 80% of people from developing diabetes! And it definitely looks like that’s possible.

Saunders: Now that we have more effective medications, we’ll need even more trained providers who understand obesity. How are we going to meet that need?

Aronne: Ultimately, obesity is such a large problem that treating it has to move into primary care. I’ve been around long enough that I remember hypertension being a disease that was treated by specialists. Hypertension medicines were hard to use, and they had a lot of side effects. You didn’t prescribe them lightly because it wasn’t clear how much benefit they offered. As it became evident that treating hypertension could prevent strokes, heart attacks and heart failure, interest grew. But it wasn’t until we had better medicines — medicines that had fewer side effects, were more effective and were easier for people in primary care to use — that treatment in the primary care setting really took off. Looking at that experience, I think that now that we have these treatments for obesity, it will move into primary care.

Saunders: We’ve made steady progress over the past 10 years, but recently developments seem to suddenly be snowballing. Is this the start of exponential growth? In another 10 years, will we be significantly further along?

Aronne: I think this is the very beginning. Remember that just a few years ago, only 2% of the population that qualified for anti-obesity medication was being treated according to guidelines. Now, as people see the benefits, they’re demanding these medications. The number of prescriptions has skyrocketed and the supply can’t keep up with the demand for them. We need to figure out the cost issue, but we also have to take into consideration how badly people want this. People don’t want to have the disease of obesity, and they will do what they can to avoid it. The demand is only going to grow from here.

A leading authority on obesity and its treatment, Dr. Louis Aronne is the Sanford I. Weill Professor of Metabolic Research at Weill Cornell Medicine and he directs the Comprehensive Weight Control Center (CWCC), a state-of-the-art multidisciplinary obesity research and treatment program.  He is the Co-Founder & Chief Scientific Advisor at Intellihealth.

The post The AMA Recognized Obesity as a Disease in 2013. How Far Have We Come in the Last 10 Years, and Where Are We Headed? appeared first on Medika Life.

Our taste for junk food high in fat and sugar has been cultivated, and it alters the brain’s reward circuitry, driving an addiction-like behavioural phenotype of compulsive overeating. But it doesn’t stop at obesity.

There is growing evidence to suggest that there is an association between the consumption of ultraprocessed foods and cognitive decline. In a cohort study of 10,775 individuals, higher consumption of ultraprocessed foods was associated with a higher rate of global and executive function decline after a median follow-up of 8 years.

Ultraprocessed foods often contain additives such as artificial flavors, colors, and sweeteners. They are typically high in calories, fat, and sugar. But it’s not simply these foods, but how our body processes food and our gut microbiota.

Research is pointing to the relationship between our gut and neurodegenerative disorders with recent studies denoting an association between Alzheimer’s and changes in the gut microbiome. The belief is that there is a link between how high fats and simple carbohydrates are processed in the gut resulting in changes in cognition.

The idea that what we eat is mind-altering has been explored for over a decade, but it is now coming to the fore. The exact pathways between impaired cognition and food choices are still under consideration.

The evidence related to neurologic disorders and emotional disturbances, such as depression, has established a gut-brain axis interaction (GBA) at work. Both healthy and unhealthy diets provide meaningful, previously unknown connections in our nervous system and our brain’s functioning. Who thought a life of hot dog eating could cause dementia? Scientists now see how careful food selection may ward off cognitive decline.

When you are next tempted to go for those highly processed goodies, do your brain a favor and pass them up. Practicing this type of personal food-selection discipline will be well worth it in your future functioning.

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The discovery that Ozempic (semaglutide) supports weight loss is not new, but the unexpected spotlight on weight loss as a side effect of a diabetes medication serves as a good reminder to healthcare providers (or a wake-up call, for some) that all medications’ potential effects on weight should be taken into account, because the opposite result — drug-induced weight gain — is more common than most practitioners realize.

A typical case

A 33-year-old woman, Jill, recently presented to my obesity medicine practice because she had suddenly started to gain weight — 32 pounds over the previous six months. Through my evaluation, I learned that she had received two Depo-Provera injections during that time. She had previously used oral contraceptive pills, but she often forgot to take her pills and wanted a lower-maintenance form of birth control. Although progestin injections work well for many women, weight gain is a known and fairly common side effect, and the timing of Jill’s weight gain suggested a causal link. As part of her weight-management plan, we discussed birth control alternatives, and she ultimately chose to switch to a nonhormonal IUD.

The OB-GYN who prescribed her Depo-Provera had not mentioned the possibility of weight gain. While it’s understandable that many practitioners don’t want to create unnecessary worry about a side effect that might never materialize, it can be extremely difficult to lose weight once it has been gained, particularly for those who already have overweight or obesity. Since many patients who don’t track their weight can gain significant amounts without realizing it, simply advising patients to monitor their weight and notify their provider if they notice an increase can prevent tremendous frustration.

Jill was on only one weight-gain-promoting medication, but I often identify two, three, or even four such culprits when taking a new patient’s history. In addition to injectable or implantable birth control, some of the most common weight-gain-promoting drugs include diabetes medications, blood pressure medications, and antidepressants. In many cases the effect is modest, but with long-term medication use for chronic conditions, even a small effect can lead to a significant increase in weight over time.

Prevention starts with awareness

What can healthcare practitioners do to help their patients avoid drug-induced weight gain? Essentially, four things:

1. Be aware. First, practitioners need to recognize how common the problem is and educate themselves about the weight profiles of various classes of drugs and different agents within classes. (The Endocrine Society’s practice guidelines for the pharmacological management of obesity include information on drugs that cause weight gain and recommended alternatives; see the original article in the Journal of Clinical Endocrinology and Metabolism, or a summary listing in Table 2 of our more recent best practices article.) As with most contributors to the multifactorial disease of obesity, the interactions are complex, and a medication’s impact on weight may vary based on a variety of physiological, genetic, and lifestyle factors. But despite some unpredictability, many medications do have a well-documented track record of promoting weight gain, and providers should be alert to this potential side effect.
2. Choose alternatives when possible. When prescribing any medication, providers should consider the drug’s weight profile in assessing the benefits and risks, and seek to avoid weight-promoting drugs when possible. Weight-neutral or weight-loss-promoting medications are available for many common conditions that are frequently associated with obesity, including type 2 diabetes, hypertension, and depression. These alternatives should be prioritized when appropriate as first- and second-line treatments — especially for patients with overweight, obesity, or metabolic risk factors. For example, for patients with type 2 diabetes, weight-loss-promoting medications such as metformin and glucagon-like peptide-1 (GLP-1) receptor agonists (semaglutide and liraglutide, for instance), or weight-neutral options such as DPP-4 inhibitors, are preferred over insulin and insulin secretagogues that promote weight gain. For patients with hypertension, weight-neutral angiotensin-converting enzyme inhibitors or angiotensin receptor blockers should be chosen over weight-gain-promoting alpha- or beta-adrenergic blockers if possible. Many antidepressants present a risk of weight gain, for example, but only one, bupropion, has been consistently shown to promote weight loss, though it’s not appropriate for all patients. When recommending changes to existing prescriptions, providers should either consult with the original prescribing physician or ensure that the patient does so. The topic of drug-induced weight gain needs to be discussed extremely carefully with patients, though, or they may feel alarmed and stop taking their medications before a plan for replacement is in place.
3. Use the minimum dose. Drugs in the same class often aren’t interchangeable, and if no appropriate alternative to a weight-gain-promoting medication is available, providers should aim to prescribe the lowest effective dose for the shortest possible duration needed to manage the patient’s symptoms. Too often, patients are started on a medication, and then the dose and duration of the drug regimen are never reevaluated.
4. Counteract the effects with anti-obesity medication. When weight-gain-promoting medications must be used, practitioners should consider adding an anti-obesity medication, in conjunction with appropriate lifestyle modifications, to counteract weight-promoting effects in their patients with obesity. Providers who don’t feel comfortable prescribing these medications can refer their patients to an obesity medicine specialist.

The challenge of reversing weight gain

Optimizing medication choices may seem like low-hanging fruit in the effort to help patients manage their weight, and in a certain sense it is: prescribing weight-loss-promoting instead of weight-gain-promoting drugs can be a relatively simple way to prevent unwanted weight gain. This is an important strategy because reversing drug-induced weight gain is not always simple.

Jill was disappointed to find out that weight gained due to medication is sometimes no easier to lose than weight gained due to any of the other myriad contributing factors. Although switching birth control stopped the increase, she didn’t immediately lose the pounds she had gained. This is such a crucial point: many patients aren’t alarmed when realize they’re gaining weight on a medication because they assume the weight will come off easily when the medication is discontinued — however, this is often not the case. Jill and I developed a comprehensive, personalized weight-management plan that is beginning to show results, but it will be a long-term effort.

There’s no silver bullet in the fight against excess weight; obesity is a chronic disease that requires lifelong management. While weight-loss-promoting medications are a valuable addition to our armamentarium, they are not a quick fix, and pharmacotherapy needs to be part of a multidisciplinary approach that also includes diet, physical activity, and behavioral modifications. So it won’t be a surprise if most of the people who recently flocked to Ozempic without proper medical supervision regain the weight as soon as they stop taking the medication.

The ratchet nature of weight gain (easy come, decidedly not easy go) makes it even more critical that healthcare providers be aware of the potential weight-related side effects of medications and adjust their prescription choices accordingly. Obesity has many complex and interrelated causes, and the more of these underlying factors we can eliminate — like weight gain secondary to medications — the more successful we will be in helping our patients move toward a healthier weight.

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First, let’s acknowledge that losing weight is difficult for almost everyone, including men, and it’s not just a matter of “trying harder,” or simply taking in fewer calories than we expend, because our bodies fight back. The human body has evolved to avoid starvation, which is why most diets don’t work: the metabolism slows, appetite and cravings increase, and a variety of other physiological mechanisms kick in to resist significant and sustained weight loss.

While this is true for anyone who wants to lose a few pounds and keep them off, obesity complicates the picture even further. Obesity is an extremely complex multifactorial disease that is associated with more than 200 medical conditions, and scientists are still working to untangle many of these intertwined, mutually reinforcing associations. But although we don’t yet understand all the factors involved, some of them do have clear connections with differences in male and female biology.

So — to return to the original question — yes, it’s actually a well-documented phenomenon: women often do have a harder time losing weight.

The many-sided role of estrogen

Not surprisingly, sex hormones are likely a significant contributor to this difference. Estrogen, in particular, affects a wide range of physiological processes.

On the positive side of the ledger, estrogen increases energy expenditure, and, through neurobiological pathways in the central nervous system, it also plays a role in suppressing appetite, leading to changes in food intake at different phases of the menstrual cycle. Interestingly, studies have shown that women are more likely to report cravings for sweet foods and men savory foods, and that age, for women but not men, is inversely correlated to cravings for fat and carbohydrates.

Most significant to the issue at hand, though, is estrogen’s contribution to the accumulation of fat in subcutaneous tissue, where it is more likely to be stored long term rather than used for fuel. This means that premenopausal women tend to have a greater percentage of body fat than men, and that this fat is harder to lose. Compounding the impact of body composition, women also typically have less muscle mass, which burns more calories than fat tissue, even at rest.

In contrast, men and postmenopausal women tend to accumulate more visceral fat, which wraps around internal organs. Although visceral fat is more readily used for energy needs — and thus easier to lose — it’s also considered more dangerous, as it is associated with increased risk of both insulin resistance and cardiovascular disease.

Visceral fat expands by adipocyte hypertrophy (the fat cells increase in size), while subcutaneous fat expands by adipocyte hyperplasia (the cells increase in number). Smaller subcutaneous fat cells can store more lipids such as triglycerides. In visceral fat, when the adipose cells reach maximum size and can no longer store more lipids, these lipids are deposited in other tissues, leading to insulin resistance. Visceral fat promotes insulin resistance via other mechanisms as well, such as the secretion of proinflammatory cytokines. The increased inflammation and higher blood lipid levels associated with excess visceral fat also contribute to many other conditions, including atherosclerosis, which can lead to heart attacks and strokes.

The increased health risk posed by visceral fat is the origin of the old rule of thumb about apple-shaped bodies (more belly fat) being more at risk than pear-shaped bodies (more fat in the hips and thighs). In fact, waist circumference is highly correlated with increased risk of type 2 diabetes and cardiometabolic disease. The risk threshold is generally considered to be 35 inches for women and 40 inches for men, with different thresholds for different populations. While people with obesity generally have excess fat in both subcutaneous and visceral tissue, those without metabolic complications often have a larger proportion of subcutaneous fat, especially in the thighs.

Other contributing factors

Genetic factors affect body weight and fat distribution as well, but the sex-specific impact is less well understood. One study, for example, showed that among mice whose sex organs had been removed, those with female sex chromosomes (XX, XXY) gained more body weight than those with male chromosomes (XY, XO), suggesting that sex chromosomes themselves play a role that is separate from the effects of sex hormones. In addition, large-scale genome-wide studies have identified a number of single-nucleotide polymorphisms (variations at a single position in a DNA sequence) associated with fat accumulation or distribution that were either significant in females but not in males or had larger effects in females than in males. These sex-specific differences account for a very small fraction of the genetic heritability of obesity (general body shape and natural “set point” weight range are highly influenced by genetics as well), but they do represent a promising avenue for further study.

Obesity is also affected by an enormous range of additional variables, including lifestyle, other physical and mental health conditions, medications, socioeconomic circumstances, sleep patterns, previous weight-loss experience, social and psychological pressures, and on and on. And while some of these factors may involve sex- or gender-related differences, the collective impact of all the factors is usually more significant than any one dimension.

Personalization is key

For this reason, an effective weight management program needs to take into account all the factors contributing to an individual’s weight gain, and the interactions between them, and provide personalized guidance based on those specific factors. Fortunately, the field of obesity medicine has made great strides in recent years, allowing us to draw on vast quantities of data to identify which combinations of interventions — including diet, physical activity, behavioral modifications, pharmacotherapy, devices, procedures and surgery — are likely to be most successful given an individual’s unique situation.

Losing weight may be hard, but biology isn’t destiny. We have the tools to alter the outcome. For those who want to take that next step, effective treatment options do exist.

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