INTRODUCTION TO OBESITY, LIFESTYLE, GENETICS and PHARMACOTHERAPY
There is little doubt among most medical and nutrition professionals, that worldwide obesity and its eventual health consequences represent the main challenge to medical systems and national healthcare expenditures in most countries. The World Health Organization (WHO), in 2022, estimated that some 1.9 billion people worldwide were overweight and some 650 million were obese. By 2030 more than 20% of the world’s population will have a body mass index (BMI) equal to or greater than 30 Kg/m2, meeting the definition of obesity. There are some 200 co-existing diseases associated with obesity, many increasing all-cause and cardiovascular mortality. Over the last two decades, this alarming trend has also impacted individuals in developing countries, and disproportionally people at the lowest socioeconomic levels in most industrialized nations. According to the WHO, far more than hunger, obesity is the major problem. Currently in the U.S. about one third of all adults have a BMI equal or greater than 30 Kg/m2, and some 20% of individuals 18 and under are considered obese since their weight is greater than 95% of their peers. The stigma, shame and adverse health consequences associated with being overweight or obese affect people of most races and backgrounds. With the recent availability of new drugs to treat obesity coupled with the emergence of novel genetic research, there is both excitement and concern about optimal treatment strategies for the individual patient. A new treatment paradigm is emerging. We are likely seeing the first generation of these new agents with subsequent drugs currently under research, perhaps even more effective, soon to follow. One may reasonably ask: Is treating obesity with pharmacotherapy the correct approach? Not long ago, humans’ daily concerns were mainly related to survival by finding food, shelter and water. Those who did so thrived and reproduced, and those who didn’t, perished. Undoubtedly, much has changed over the last two hundred years. For most on earth, the daily pressure to survive has been removed. Overabundance and overconsumption of poor-quality food is all too commonplace and a first in human history. Much has been learned about obesity over the last one hundred years. Clearly, this current phenomenon of widespread obesity and associated diseases is extremely complex. What can be done about it?
In 1981, Drs Hugh Trowell and Dennis Burkitt, missionary physicians who had worked and taught in hospitals and medical schools in Kenya and Uganda, published a list of what they called “Western Diseases”. These were mostly non-infectious chronic diseases associated with western diets and lifestyles increasingly prevalent in the mid to latter-20th century in Europe, North America and other urban centers in first world nations. At the time of publication, most medical experts accepted the list. The two investigators had obtained their data from many years of personal observation, surveys of hospital inpatient records, worldwide medical journal publications and the valuable opinions of more than thirty doctors from five different countries. This collaboration resulted in the publication of the book: “Western Diseases: Their Emergence and Prevention.” The initial list of diseases was a provisional one. The researchers agreed that in time, other diseases would make it on the list. These, we now know, include inflammatory bowel disease (Ulcerative Colitis, Chron’s Disease), autoimmune disorders and various forms of dementia. The original list included metabolic and cardiovascular diseases such as stroke, myocardial infarction, hypertension, type 2 diabetes, deep vein thrombosis and pulmonary embolism, dental caries and periodontal disease, multiple gastrointestinal diseases, various cancers such as breast, lung and colorectal, gout and subacute combined degeneration. The investigators observed that as developing nations became more “westernized”, mostly by including in their diet food products from the west, the incidence and prevalence of these diseases rapidly increased. They had first-hand knowledge of the emergence of such western diseases in far off places where indigenous populations had mostly lived for millennia as hunter-gatherers. As western products were introduced, made up of processed foods, with added sugar, white flour, as well as sweetened beverages and cigarettes, indigenous populations worldwide, predictably became sick. The adoption of western diets and more urban sedentary lifestyles in the 20th, and now in the 21st century, along with government-food industry sponsored nutrition recommendations, the 1992 food pyramid, are the root causes of the present overweight and obesity problem. The abundant supply of food industry products with added sugars, low in healthy fats, replete with chemicals deleterious to human health and deficient in nutritious ingredients, mostly advanced in the 1980s and 1990s to the population at large, has resulted in the present worldwide obesity epidemic. With the fast-growing number of patients diagnosed with type 2 diabetes mellitus and pre-diabetes (~40 million and some 100 million respectively in the U.S.), the CDC has estimated that today young adults and children will likely live fewer years than their parents, a new trend indeed.
Recently, aside from lifestyle modification, some older medications, and bariatric surgery, a new treatment for obesity has been the focus of enormous publicity. The FDA approved pharmacotherapy consisting of a GLP1-RA (Ozempic and Wegovy containing semaglutide) or the dual agent, GLP1-RA/GIP (Mounjaro and Zepbound both containing tirzepatide), injected subcutaneously once a week for type 2 diabetics and for overweight or obese individuals, has created immense public demand. Much has been said and written, both positive and negative, by the mainstream media, social media platforms, cable channels, podcasters and others, about the effectiveness and adverse side effects of these drugs. These medications, initially developed to treat type 2 diabetes mellitus, stand to be among the most successful drugs ever launched, mostly due to the significant weight loss noted in most, at least while the individual is on the weekly correct dose. Several well-designed, placebo controlled, peer reviewed published articles with these agents have demonstrated the significant cardiovascular and metabolic benefit of these agents in high-risk obese diabetic and non-diabetic patients with established cardiovascular disease. But the main daily demand for these agents, in most primary care clinics, is for weight loss in lower cardiovascular risk individuals. Should all these overweight and obese people be prescribed such an agent? Who is more likely to lose weight and keep it off? Who may be a non-responder? At the root of all this, the cause or causes of being overweight or obese remain controversial. We now know that obesity is far more complex than the imbalance of intake versus expenditure of calories. For some, obesity is a disease that is mostly determined by biology, in other words, genetics. For others, obesity is mostly the result of environment, that is, lifestyle choices. Still, with recent eye-opening research information from the relatively new field of Nutrigenomics, most now believe in the significant contribution of both genetics and lifestyle. With more than two thirds of the U.S. adult population currently considered overweight (BMI 25.1-29.9 Kg/m2) or obese (BMI greater or equal to 30 Kg/m2), these are all critically important topics for discussion. One may very well ask: When did obesity start?
HUMANS AND OBESITY
Let’s briefly examine human history. Were there obese individuals in prehistoric eras? Interestingly, a “Venus” statute discovered in 2008 in southern Germany, estimated to be about 35,000 years old, appears extremely obese. With large breasts and buttocks, experts believe it was associated with fertility. It is likely that more than 10,000 years ago, obesity was extremely rare since most populations were hunter-gatherers. Current societies of hunter-gatherers, such as the Sab people of Botswana, Pygmies in central Africa, Baka of Cameroon and the Batek in Malaysia, are an indicator of body types in prehistoric times. They were mostly thin and about 5 feet tall with an average BMI of 20 Kg. /m2. Surprisingly, researchers in the field estimate about 70% of these people consumed more than 50% of their calories from animal meats and fish, and the rest from vegetables and fruits as well as tubers. Only about 14% of pre-historic people consumed more than 50% of their calories from vegetables and fruits. Since most tribes insisted on sharing the meat and fish equally among all members of the tribe and combined with 3 to 5 hours of daily physical activity, obesity was practically non-existent. Over thousands of years, hunter gatherers evolved physiologically to retain fat since their greatest risk, aside from infections and violent deaths, was famine and starvation. In times of abundance, they became adept at storing fat. In 1962, Dr. James Neel proposed the “thrifty gene” hypothesis to explain the observed genetic predisposition, in certain populations such as the Pima Indians, to develop some or all the components of metabolic syndrome (obesity/insulin resistance/diabetes/hypertension/dyslipidemia) that eventually result in cardiovascular and other western diseases. He proposed an evolutionary survival advantage in times of scarcity, in that humans would store calories as fat. Conversely, in times of abundance and overconsumption, obesity and metabolic syndrome would ensue. It was also proposed, such individuals would also be genetically predisposed to exert or “burn” fewer calories during regular daily activity. Experiments in mice have confirmed that obese animals are better able to withstand food deprivation than normal weight mice. What about our ancestors?
Research by Pontzer et al, Epub 2012 Jul 25, in their paper on hunter-gatherer energetics and human obesity, has demonstrated that energy expenditures between hunter-gatherers and Westerners are the same. The average metabolic cost of walking or resting of traditional Hazda foragers, after controlling for body size, was no different than that of Westerners. This likely means, over thousands of years, we humans have evolved daily energy expenditure, as a physiologic trait that is independent of cultural differences. Hence, genetic predisposition to obesity, less daily physical activity, more access to high caloric density foods and daily overconsumption of such foods, gradually results in worldwide obesity. When can one point to the start of this trend?
Obesity likely started some 10,000 to 12,000 years ago when the agricultural revolution first developed in Mesopotamia’s fertile crescent, then spreading gradually to western Europe and other places. Domestication of grains and animals resulting in food surpluses and a more sedentary lifestyle in settlements, both made overconsumption possible for the first time in human history. At the same time, those that remained in a hunter-gatherer lifestyle avoided obesity. Subsequent technological developments such as the steel roller mill in the 19th century, the production of processed foods, mass transportation and marketing of such foods, all made overconsumption more likely, especially for more affluent societies. The breakdown of grains and other carbohydrates made human digestion easier, adversely impacting sugar and lipid metabolism and adiposity, and creating more rapid hunger and craving for such products. Over the last 10,000 years, agricultural societies have had more time for the interplay between the brain’s energy regulators, liver metabolism, pancreas, skeletal muscles and gut bacteria (biodome), to adapt to such diets with more daily sugars and fats, and a more sedentary lifestyle, than hunter-gatherers who maintained their ancestral dietary and lifestyle customs. Over the last 500 years, with the gradual introduction of western diets to un-adapted indigenous populations all over the world, as seen with European colonization in Africa, America, Alaska, Caribbean Islands, Southeast Asia and South Pacific Islands, the result is a sharp increase in obesity and “Western Diseases”. Indigenous populations in the Americas, mostly having migrated in waves after the last glacial maximum, starting more than 16,000 years ago, from hunter-gatherer populations in Manchuria, Mongolia, Northern Siberia and east Asia, for the most part continued with a hunter-gatherer lifestyle. These diverse populations were not exposed to western diets till very recently. They too, have not adapted to high sugar, high fat, processed food diets and overconsumption of these foods that predispose to visceral obesity, and higher rates of type 2 diabetes, cardiovascular disease and the other western diseases.
Sadly, this situation will continue to worsen. Globally we are producing more food than is needed. Food subsidies in the U.S. and Europe are fueling significant overproduction, affecting developing nations. Being overweight and obese has become more the norm rather than the exception. Now people around the world can purchase more calories for the same cost as western Europeans could decades ago, all too often resulting in overconsumption. Populations that descended more recently from hunter-gatherer societies and have adopted western lifestyles over the last 100 years, have not entirely “adapted” to such foods from a metabolic standpoint. They are far more likely to develop the dreaded Western Diseases, as observed by Drs. Trowell and Burkitt in the mid-20th century. On an aside, what about the 850 million that are hungry? This is not because of a lack of global food supply, but a lack of access to food on account of war, local conflicts and politics, natural disasters, animal and plant pests, and unfair international trade. Some are local and others are global issues that require the political willingness to eradicate. The factors that contribute to the overweight and obesity epidemic, at least in some more than others, do appear to also have a genetic component. Let’s now examine what we currently know about the genetic contribution to being overweight or obese.
GENETICS AND OBESITY
In the aftermath of the Human Genome Project, more recently, Genome Wide Association Studies (GWAS) and Epigenome Wide Association Studies (EWAS), much has been learned. No doubt this is an extremely complex topic, with ongoing worldwide research, so one needs to be careful in assigning definitive causality, as if it were written in stone. We now know that there are genetic causes of obesity. The relatively new field of Nutrigenomics is the study of genetic and dietary factors on health. Multiple published trials on the effect of single nucleotide polymorphisms (SNPs) are yielding tremendous new insight into an individual’s risk of developing obesity and the effect of diet and other interventions in weight loss. It has become evident that obesity is multifactorial with a definite genetic correlation plus an environmental factor. A recent study published in Nutrition, 16 November 2023, titled: Genetic Variant Pael Predicts Obesity Risk and Efficacy of Diet in Weight Loss. These investigators assessed 102 SNPs in genes associated with obesity such as FTO, MCM6, HLA and MC4R. The study revealed that in a population of 9372 multiethnic participants, there were 10 SNPs associated with high BMI risk. Also 4 SNP’s that were female specific genetic markers for obesity. Most interesting was the finding that 2 SNPs predicted successful weight loss with adherence to diet. Two SNPs predicted individuals who would be more likely to lose weight with a gastric balloon or bariatric gastric sleeve procedure. Clearly genetic factors influence BMI and weight loss response to exercise. Other studies in this field have demonstrated that BMI is associated with specific SNPs across ancestries and sexes. Insight from another study in Taiwan revealed SNPs that “cause” visceral obesity versus global obesity, and influence neural pathways that affect BMI, % body fat and waist to hip ratio. A genetic obesity risk may be derived from the number of SNPs that an individual possesses. A patient without or just a minimal number of high-BMI associated SNPs may still become obese with a poor lifestyle. However, that patient is less likely to develop obesity than an individual with many of the high-BMI associated SNPs who follows a “healthier” lifestyle. This latter individual may possess a small contribution from a variety of different SNPs, each “adding” risk to becoming obese. We are entering the era of individualized medicine with such genetic information providing medical providers and nutritionists with more precise tools to optimize a treatment strategy. As more genetic data on SNPs becomes readily available and affordable, we in the medical field can offer the best treatment approach, beyond diet and exercise, for diverse populations worldwide. Are there other genetic issues that result in obesity?
The clearest examples are the “Syndromic Obesity” patients such as individuals afflicted by Prader-Willi Syndrome (paternal chromosome mutation 15q 11-13 deletion), Bardet-Biedel Syndrome (16 genes affected), and Albright’s Lipodystrophy (mutation in the leptin gene at chromosome 7 q31.3). There are others with “Monogenic Obesity” mostly seen in patients with single gene mutations. The most common of these are those in the leptin signaling pathway. Leptin is a hormone predominately synthesized by adipocytes (fat cells) whose main role is to regulate long term energy balance. It plays a major role in inducing appetite, feeding behavior and satiety. High levels indicate to the human brain, via leptin receptors located in the regions that control hunger, that energy reserves are high, thereby inducing satiety. Mutations along this pathway result in hunger and overfeeding. The most common of these leptin pathway mutations is the mutation at the MC4R (hypothalamic receptor for alfa-melanocortin stimulating hormone). This occurs in 0.5% to 6% of patients with obesity. In fact, some 60% of inherited obesity is polygenetic, with multiple genes contributing to varying degrees. Examples include mutations in the adrenergic pathways that impair energy utilization and lipolysis. Also, mutations of the gene that regulates serotonin synthesis impair appetite control and energy balance. GWAS, to date, has found approximately some 250 genes that play a role in childhood and adult obesity with the most frequent being single mutations in the FTO gene (fat mass and obesity associated gene) located in chromosome 16. FTO mutations are associated with obesity, depression and ADHD. Such individuals exhibit attenuated autoinhibition to food consumption. They have altered hunger versus satiation balance, and lack of appetite control with resulting in continued feeding. FTO gene studies since 1999 have uncovered the impact of such mutations on insulin resistance, gluconeogenesis, elevated triglycerides, adipogenesis, lipogenesis, decreased fatty acid oxidation, Non-alcoholic fatty liver disease, mitochondrial disruption, oxidative stress and eventually type II diabetes mellitus.
What about epigenetics? This is where biology and environment intersect. FTO mutations play a role in epigenetic alterations that result in methylation or demethylation of an individual’s DNA causing upregulation or down regulation of various genes involved in glucose and lipid metabolism. If an individual possesses multiple such adverse FTO gene mutations, it becomes more difficult to maintain optimal weight. However, environmental factors play a significant role in modifying epigenetic histone proteins (proteins that surround the DNA) via histamine acetylation. These proteins turn “on” or “off” various genes, for example, resulting in fatty acid synthesis, adipogenesis and fat storage. In other words, epigenetic proteins may be modified by the environment, and they in turn increase or decrease specific gene expression. Mediterranean and other refined sugar restricted diets, fasting, regular exercise, probiotics, prebiotics, destressing, optimal sleep patterns, connecting with family and friends, and others, are all behaviors that modify the epigenome and subsequently alter gene expression favorably. Adopting and adhering to such positive lifestyle patterns is of paramount importance, especially for individuals with unfavorable genetic mutations. Health education on lifestyle and holding the individual accountable from preteen years and forward, remains, in this doctor’s opinion, as the best tactic to prevent “Western Diseases.” This is essential for young women in their childbearing years since maternal obesity, poor nutrition and exposure to toxic substances such as organochlorides, polycyclic aromatic hydrocarbons and cigarettes, cause gestational diabetes, and through fetal programming insulin resistance in the newborn. In addition, the use of antibiotics in the first year of life may also predispose to eventual obesity and a fatty liver. Interestingly, recent evidence demonstrates that paternal overnutrition, prediabetes, high sugar and low protein diet, are all linked to epigenetic fetal modification and obesity in the child. No doubt, as we have noted, genetics plays a critical role in obesity in a fair number of individuals, some in a minor and others in a major way, depending on epigenetic factors, the number of high-BMI SNPs, the presence of favorable weight loss SNPs, and environmental factors. But it is also clear, personal choices, such as how much sugar one consumes daily, how much one exercises consistently, and others as noted previously, with their proven impact on epigenetic modification and signaling, all play an important role in avoiding the dreaded “Western Diseases”. Can we influence epigenetic factors early in life as part of an obesity preventive strategy?
As a society, especially in at-risk minority communities, we must provide early nutrition education starting in elementary and middle school, parent nutrition education, safe playgrounds, afterschool physical activity programs, improve the quality of school lunch programs, limit social media use, optimize the use of the Supplemental Nutrition Assistance Program (food stamps), and provide affordable healthy food choices. I must admit that this appears to be a simplistic approach, but it is one that has hardly been attempted on a widespread basis. There is emerging evidence that the approach on nutrition education in elementary school children works. Dr. Valentin Fuster, Editor-In-Chief of the Journal of the American College of Cardiology, launched such a program in Spain, Colombia and even Harlem, New York. This type of strategy may well serve as a template for many at risk communities to implement. The elephant in the room is the role of the food industry. Can we, as a society, demand better products? If we do not, it is likely the U.S. National Healthcare Expenses by 2030, as CMS projects, will be almost 7 trillion dollars a year. Unless we start to prevent disease, our existing medical model will not be sustainable, with quality of care declining and millions left without coverage. Collectively, the food industry, especially fast-food businesses, should be incentivized to significantly cut added sugars, saturated fats and other chemicals in their products. Marketing such fast food and high-sugar content foods to children needs to be critically assessed to determine reasonable boundaries. The term “organic” should be redefined to a higher standard, avoiding loopholes and the industry held accountable for animal products, vegetables and fruits. Perhaps some of these strategies can be achieved via a reverse taxation program (RTP) that rewards companies that decrease sugar, saturated fats, salt, and other unhealthy items from their products. Also, the financial conflict of interest relationships between the food industry, medical institutions and our government agencies all need to be disclosed and severed. As an example, the American Heart Association and the American Diabetic Association should not be endorsing products or beverages that do not meet strict criteria as proven to be healthy, especially for children. Social media influencers, including artists and athletes, should be encouraged to promote healthy foods and positive lifestyles. In summary, the goal of these strategies, if implemented early, is to positively impact epigenetic influence on gene expression.
GLP-1 AGENTS IN OBESITY AND CARDIOVASCULAR DISEASE
What about the millions who are currently overweight or obese with one or more risk factors such as type 2 diabetes, hypertension and dyslipidemia, and have not succeeded with various diets and exercise programs? What should a concerned provider recommend? What about type 2 diabetics who are overweight or obese and have already experienced a cardiovascular event such a stroke, heart attack or have undergone a procedure such as a stent or even coronary bypass surgery? What’s the data on such patients? Today, most physicians, especially cardiologists, focus on decreasing present and future adverse cardiovascular risk in patients. At our disposal we have proven prediction models for the next 5 to 10 years which provide insight into an individual’s likelihood of having a major cardiovascular event, including heart attacks, strokes and cardiac death. Hence, beyond intensive lifestyle intervention, beyond weight loss, we cardiologists prefer to treat patients with drugs that have demonstrated a significant decrease in such life-threatening events. So, what’s the data from cardiovascular outcome trials that clearly demonstrate GLP-1 RAs decrease such events in diabetics with established cardiovascular disease and in the overweight or obese without diabetes? What about data on individuals who are just overweight or obese without cardiovascular disease or diabetes in terms of weight loss as an end point? Which of these different individuals, according to the published literature, who do not have a contraindication, should be prescribed one such agent? If so, for how long? One may reasonably ask who truly benefits the most and are the positive results sustained long term after the medication is withdrawn? Understanding that such drugs currently cost about $900 and up to $1,400 per month, it is important to answer these questions by reviewing peer reviewed published data in the most respected journals worldwide.
Let’s first focus on data that demonstrates a significant decrease in the triple end point of cardiovascular death, non-fatal heart attacks and non-fatal strokes. I will summarize 2 such trials. SUSTAIN-6 was published November 2016 in the New England Journal of Medicine. It was performed in 20 countries at 230 sites, enrolled 3297 type 2 diabetic patients, 50 years or more with established cardiovascular disease or chronic renal disease, or 60 years or more with at least one cardiovascular risk factor, 77.6% women and 93.1% white. On average the participants weighed 92 Kg., had had type 2 diabetes for 14 years and their HbA1c was 8.7% (considered uncontrolled per the American Diabetic Association and others). About 83% (2735) had established cardiovascular disease or chronic renal disease or both. This was a placebo-controlled trial with semaglutide 0.5 mg or 1.0 mg injected weekly for 104 weeks. The primary end point was the composite of cardiovascular death, non-fatal stroke and non-fatal myocardial infarction. The results were significant with respect to the primary end point with an event rate of 6.6% for thesemaglutide arm versus 8.9% for the placebo group. This represented a 26% reduction in events. Most of the semaglutide benefit was the significant decrease in non-fatal strokes (1.6% versus 2.7% or a 39% event reduction) and in non-fatal myocardial infarction (2.9% versus 3.9% or a 26% event reduction). The average weight loss on semaglutide was 15.2% from baseline versus 2.6% in the placebo patients. Some 77% experienced more than 5% weight loss with semaglutide versus 34% with placebo. In actual kilograms the average amount of weight lost from baseline on semaglutide 0.5 mg and 1.0 mg doses was 3.6 Kg. and 4.9 Kg. respectively, vs. placebo 0.7 Kg. and 0.5 Kg. These amounts include 23% of participants that lost less than 5% of weight on semaglutide therapy. There were also more gastrointestinal side effects, such as nausea, diarrhea, vomiting with semaglutide 0.5 mg and 1.0 mg, with approximately 11.5% and 14.5% respectively, vs. 5.7% and 7.6% on placebo, resulting in withdrawal from the study. In summary, per every 1000 similar patients, overweight or obese middle-aged diabetics with established cardiovascular disease, treated with semaglutide for 2 years, there will be approximately 100 fewer heart attacks and 110 fewer strokes. No significant cardiovascular or all-cause mortality benefit was observed on semaglutide. Cardiometabolic parameters including blood glucose control, lipid and blood pressure all improved on the treatment arms. Also, renal endpoints were significantly better on semaglutide. Clearly, with proper patient selection and education, this trial, in high-risk individuals, semaglutide was effective in cardiovascular event reduction, weight loss, renal endpoints and metabolic parameters. As noted above, providers need to consider that a significant number of patients will be non-responders and others will not tolerate the drug due to untoward side effects. Alternative strategies that include stricter dietary guidelines, physical activity and perhaps older FDA approved weight loss drugs can be instituted, even in combination with a maximally tolerated dose of a GLP-1 agent. Other questions remain from the SUSTAIN-6 trial. Can one extrapolate the findings to obese diabetic minorities (Blacks, Hispanics, Asians and others) with established cardiovascular disease who were not enrolled in this trial? How about in younger or much older individuals? How long should a patient stay on the medication after the initial 2 years? Will some or most regain some or all their weight back after drug discontinuation? Is there a continued cardiovascular benefit long after drug termination? Or is there emerging data that points to “lifelong” treatment in some or most of these high-risk individuals? What about this treatment in obese non-diabetics with established cardiovascular disease?
The SELECT Trial was another cardiovascular outcome trial that examined the effect of semaglutide in obese non-diabetic patients with established cardiovascular disease. It was published in the NEJM in November 2023. It was a multicenter, double blind, randomized, placebo-controlled study that enrolled 17,604 adults with an average age of 62 years, 28% females, to receive subcutaneous weekly semaglutide initiated at 0.24 mg and titrating every 4 weeks to a maximum of 2.4 mg or the maximally tolerated dose versus placebo. The mean BMI was 33.3 Kg/m2, 66% were prediabetic and 77% reached the target semaglutide dose. The primary end point, like SUSTAIN-6, was the composite of cardiovascular death, non-fatal heart attack and non-fatal stroke. The mean exposure to semaglutide exposure was 33 months and follow up was 39.8 +/- 9.4 months. The primary end point occurred in 6.5% in the semaglutide group and 8.0% in the placebo group. This represented a 20% decrease in events. Per 1000 patients treated, 150 fewer events would be predicted to occur in the treatment arm. Adverse events that resulted in discontinuation of the trial product occurred in 16.6% in the semaglutide arm and 8.2% in the placebo group. As expected, most of these were gastrointestinal in nature. This was not surprising on account of the higher semaglutide doses employed during the trial (1.7-2.4 mg). The semaglutide group also had significant results on multiple fronts. There was a 15% decrease in cardiovascular death (2.5% vs. 3.0%), a 28% decrease in non-fatal heart attacks (2.7% vs. 3.7%), and an 18% reduction in cardiovascular death or heart failure hospitalization (3.4% vs. 4.1%). Per 1000 patients treated over approximately 3.3 years, one could expect 50 fewer cardiovascular deaths and 100 fewer heart attacks. Also, 3.5% of semaglutide patients vs.12% on placebo became diabetic during the trial. The mean change in body weight at 104 weeks was -9.4% on semaglutide vs. -0.9% on placebo.
The findings from the SELECT Trial, from a cardiovascular prevention standpoint, support the use of a GLP-1 RA in obese non-diabetic patients with established cardiovascular disease. As outlined above, SUSTAIN-6 also demonstrated a significant cardiovascular benefit of semaglutide in obese diabetic patients with established cardiovascular disease. Prior studies of lifestyle and drug interventions have not demonstrated a significant cardiovascular benefit in reducing cardiovascular events in overweight and obese patients. SUSTAIN-6 and the SELECT trial have expanded our knowledge in the treatment of these high risk obese diabetic and non-diabetic patients. The beneficial effects of this GLP-1 RA agent are not entirely understood. These are likely related to the positive effects on an individual’s neurohumoral and metabolic milieu, resulting in reduction of systemic inflammation, oxidation, atherogenicity and thrombogenicity. These probably contribute to the observed improvement on the multiple cardiometabolic parameters that in time are known to result in cardiovascular events, including premature death. Similar trials with cardiovascular end points using a GLP-1 RA/GIP dual agent are on-going to assess if this agent also demonstrates a significant reduction in cardiovascular outcomes in obese diabetics with established cardiovascular disease (secondary prevention) and in obese non-diabetics at high risk for such events (primary prevention). This agent, tirzepatide, in various trials compared to placebo and insulin, has already demonstrated significant weight loss (~10%-21%), on average greater then semaglutide (by 5-10%), reduction in HbA1c, blood pressure, diabetic dyslipidemia and inflammatory markers. It is likely that soon, these on-going tirzepatide trials will also demonstrate cardiovascular positive preventive results in obese patients with and without diabetes and preexisting cardiovascular disease.
How about using these agents with weight loss as the main endpoint? Multiple such studies have been conducted and published. Here I outline several trials. The first was in obese, nondiabetic patients, without established cardiovascular disease. The STEP 1 trial published 3-28-2021 in the NEJM enrolled overweight or obese patients for 68 weeks, double blind, placebo controlled, to receive semaglutide (0.25 mg titrated monthly up 2.4 mg) versus placebo. Both groups received lifestyle counselling (reduce daily caloric intake by 500 Kcal and walk 30 minutes or more a day, 5 times a week), and 43% of the participants were prediabetic. The primary end point was weight loss. The 1306 patients randomized to the semaglutide arm lost a mean of 14.9% of their starting weight versus 2.4% of the 655 placebo patients. About 86% of the semaglutide patients lost more than 5% of their weight versus 31.5% of the placebo patients. Also, 69% of the semaglutide patients lost more than 10% of their weight and 50% lost more than 15%. The semaglutide patients had significant improvements in cardiometabolic parameters. Gastrointestinal side effects causing drug discontinuation occurred in 4.5% of semaglutide participants versus 0.8% of placebo patients. Once again this was a positive trial for overweight or obese non-diabetics, mostly white participants. Note that about 14% would be considered non-responders since they lost less than 5% of their initial weight, and almost 5% stopped the medication due to drug intolerability.
The STEP 2 trial was a 68-week placebo-controlled study in 1210 overweight and obese type 2 diabetic adults, randomized to receive weekly semaglutide 2.4 mg, semaglutide 1.0 mg or matching placebo. Similar lifestyle counselling was implemented as in STEP 1 and the primary end point was weight loss from baseline. The results were 9.6%, 7.0% and 3.4% weight loss from baseline for the three groups. The 2.4 mg dose had the higher weight loss and the most improvement on cardiometabolic and diabetic parameters. These findings indicate about a third less weight loss in diabetics than non-diabetics, an observation consistently noted with other weight loss medications. It appears diabetics have lower energy expenditure, although the exact mechanism is not yet well understood. Could it be that diabetics have a fewer number of functional GLP-1 receptors, or that these receptors do not consistently respond to the drug? The GLP-1 receptor is a 463 amino acid G protein coupled structure with 8 hydrophobic transmembrane domains located throughout multiple organs, including the brain, heart, arteries, arterioles, pancreas, gastrointestinal tract, lungs, and kidneys. Endogenous GLP-1 is synthesized by intestinal L cells in response to a meal. Then it is secreted into the bloodstream and engages systemic GLP-1receptors, causing multiple beneficial effects at each of the above organs. Of importance for weight loss are the positive effects on the brain (inducing early satiety and decreased food intake), on the stomach (delays gastric emptying and slows bowel motility) and the pancreas (increases insulin secretion, beta cell proliferation and survival and decreases alfa cell glucagon secretion). All these effects cause early satiety and ultimately less food consumption, unless the patient is a non-responder. GLP-1 has a short life as it is constantly destroyed by the enzyme dipeptidyl peptidase-4 (DPP-4) circulating in the blood. Is it possible that diabetics have some degree of “GLP-1 Resistance”, perhaps analogous to type 2 diabetics being insulin resistant? Mutations of the GLP-1 receptor, or fewer number of these, especially in long-term diabetics, or inadequate downstream cellular signaling due to intracellular inflammation, or rapid metabolism of GLP-1 by DPP-4, or mitochondrial dysfunction, or other factors. Some or all of these may explain why some patients only “respond” at the highest doses of these drugs to overcome such resistance. Could these factors explain why some 7-10% of patients do not respond at all to a GLP-1 RA agent, and why another 5-16% lose less than 5% of their initial weight? It is evident that for many such patients, these agents are not a panacea. These and other questions are certainly the subject of future investigations.
The STEP 3 trial enrolled 611 non-diabetics to maximize weight loss with semaglutide 2.4 mg injected weekly versus placebo. These individuals received intensive behavioral therapy, 30 visits with a nutritionist over 68 weeks, and a 1000-1200 Kcal/day diet during the first 8 weeks. At 68 weeks, semaglutide treated patients lost 16% of their initial weight versus 5.7% in the placebo group. The addition of intensive behavioral therapy attained the most weight loss in the first 12-16 weeks. This trial could serve as a practical template for clinicians to determine early, within the first 12-16 weeks, which patients adhere to the recommended intensive lifestyle intervention and have a concomitant beneficial response to the GLP-1 agent by losing more than 5% of their initial weight.
Step 4 was a trial that enrolled 803 obese adults without diabetes with a 20-week run-in period on semaglutide 2.4 mg injected weekly. This resulted in a 10.6% reduction in weight in the initial run-in period. Then, for the remainder of the study the participants were randomized to continue semaglutide versus placebo. 48 weeks after randomization, the semaglutide treated patients lost an additional 7.1 Kg, resulting in a net 17.1% weight loss and the placebo group regained 6.1Kg, resulting in a 5.0% net loss from the start of the study. After randomization, cardiometabolic parameters worsened in the placebo group. This study indicates that weight regain is likely when semaglutide is terminated. An analysis of 327 patients from the STEP 1 study noted that 52 weeks after stopping semaglutide, these individuals regained 11.6 % of their prior 17.3% reduction from baseline weight. These findings are concerning. This phenomenon has been observed by multiple clinicians in community clinics treating such patients. Some feel that there is a case to be made for continuing semaglutide indefinitely. Does the long-term medication cost justify such a strategy? And if so, in which patients?
Another trial, titled: “Weight Loss Outcomes Associated with Semaglutide for Patients with Overweight or Obesity”, was published online in JAMA, NetwOpen, 2022, Sept. 19, 2022. There were 175 patients enrolled, 75.4% women, average age 49 years, 88% white. The patients received semaglutide 1.7 or 2.4 mg injected weekly. The study lasted 6 months and the primary end point was weight loss at 3 and 6 months. The 175 patients that completed the 3 months lost 5.9% of their initial weight and 10.9% at 6 months for the 102 that completed the protocol. Importantly, 44% of the participants tolerated the 1.7 mg and 2.4 mg dose, while 48.6% had adverse gastrointestinal side effects with 2.9% stopping the medication and another 8.6% reducing the dose or staying at a lower dose level. This small, short-term study demonstrates that significant weight loss can be attained in 3-6 months. Could this be a better strategy, a 3-to-6-month treatment plan, and if the patient does not lose at least 5% of their initial weight, they are considered “non-responders”, and the drug is stopped. In combination with intensive behavioral therapy this could become a protocol for non-diabetic obese patients seeking mainly to lose weight, at least in the short term. The question remains as to how much weight these individuals may regain over the following 6 to 12 months when the drug is discontinued.
A meta-analysis of 13 randomized clinical trials, placebo controlled, that enrolled a total of 3794 obese non-diabetic patients with semaglutide from 1.0 to 2.8 mg weekly injections versus 2044 in the placebo arms. The average percent weight loss was 10% and the BMI on average decreased 3.19 points. Approximately 7% pf these patients were non-responders in that by 12 weeks of treatment they lost less than 5% of their initial weight. Once again, such findings demonstrate that for most individuals this GLP-1 RA was effective in promoting weight loss. Tirzepatide has also been shown to be effective in weight reduction in obese diabetics in multiple clinical trials (SURPASS-1, 2, 3, 4 and 5). These trials were from 40 to 52 weeks and the average weight loss was higher with increasing weekly drug dose (~7.0% at 5mg, ~9% at 10 mg and ~11% at 15mg). The SURMOUNT 1 trial was conducted in obese non-diabetics for 72 weeks. As with semaglutide, the percent weight loss was higher in these patients than in diabetics, and at the higher dose (~15% at 5mg, 19.5% at 10 mg and 20.9% at 15 mg). Placebo patients lost 3.1% of their initial weight. The most common adverse side effects with this agent were gastrointestinal, mild to moderate, in about 2.6% in the placebo group and 6.2% in the tirzepatide arm. The percentage of patients that lost more than 20% of their initial weight was over 50% of the tirzepatide (10mg and 15 mg) groups. Only 3% of the placebo patients lost more than 20% of their starting weight. This amount of weight reduction also improved most cardiometabolic parameters and liver fat content. The SURMOUNT 4 trial enrolled non-diabetic overweight and obese adults and after an open label initial 36 weeks, gradually increasing the weekly dose once a month from 2.5 mg up to 15 mg. Mean weight loss was 20.9%. Participants were then randomized to receive tirzepatide 15 mg weekly vs.placebo. The placebo group experienced 14% weight gain while the tirzepatide group lost an additional 5.5%. Undoubtedly, this dual GLP-1/GIP agent has significant weight loss in obese diabetics and non-diabetics for up to 88 weeks.
As we have noted, obesity is a complex heterogeneous disease. Most people have tried different approaches to lose weight and maintain it off, including pharmacotherapy and fad products or diets, only to meet with disappointment. Unfortunately, in most patients this tragic cycle repeats itself over and over. There are individuals with a definite monogenic or polygenic predisposition, and many others have adverse SNPs present in their genetic make-up, and yet for most, it’s a mixed bag. One can say obesity is also related to the environment and lifestyle choices. A person’s ancestry, cultural dietary heritage, family, friends, hobbies, frequency of home cooking vs. restaurant dining and fast-food consumption, mental health, substance abuse, metabolic, neurologic and orthopedic health status, stress level, age, gender, marital status, educational level, sedentary versus physically active employment, sleep pattern, socioeconomic status, access to affordable quality foods, access to high quality healthcare, among other factors, all impact being overweight or obese. Finally, the interplay of a complex system of neurohormones that increase appetite such as AgRP/NYP synthesized in the arcuate nucleus of the hypothalamus, Ghrelin secreted mostly in the stomach, but also in the brain’s arcuate nucleus and pancreas, as well as endorphins/enkephalins secreted by the prefrontal cortex that activate the mu-opioid receptors, all result in the inhibition of the appetite suppressor alfa-MSH, resulting in the sensation of hunger, craving and eventually eating to release the pleasure neurohormone dopamine. Food, especially sweets and fats are more likely to release dopamine than vegetables and fiber. Hormones such as leptin and insulin play an inhibitory role in the above complex circuitry, may not be as effective in many individuals, depending on their genetic predisposition, lifestyle and epigenetic modifications, on account of insulin resistance, as in diabetics, and in others varying degrees of leptin resistance. In patients experiencing mental health issues, such as depression and anxiety as well as emotional stress, may experience frequent overeating foods high in sugar and fat content, including binging, to soothe their “feelings” by activating the neurohormonal system that ultimately releases dopamine. Making this entire system more complicated is the role of the liver. The energy sensors in liver cells, via the biochemical reactions and enzymes orchestrated in the citric acid cycle, also known as the Krebs Cycle, not only release energy from consumed nutrients, but also determine the balance between synthesis and utilization of glucose and fatty acids. These finely tunes reactions have evolved and adapted over millennia in humans and our ancestors, depending on our environmental challenges. Some, as noted in those from predominant hunter-gatherer individuals, have a greater enzymatic liver predisposition to synthesize and store fat, and develop type 2 diabetes, especially when there is over consumption of various foods in combination with a sedentary lifestyle. Others, such as those from an agricultural society ancestry have adapted to regular consumption of sugars and animal fats, are less likely to develop obesity and type 2 diabetes. This phenomenon is clear when one examines the incidence here in the U.S. of type 2 diabetes in Caucasian populations versus native Americans and Latinos. Of course, there are millions in the U.S. that have both traits since we are a multicultural society with significant mixing of the gene pools. Another factor is the role of the gut, otherwise known as our biodome. The trillions of gut bacteria, the so-called prebiotic bacteria, play a critical role in health. Dietary fiber from vegetables, fruits, legumes and whole grains is fermented by gut bacteria to produce short chain fatty acids that produce a variety of positive health benefits, including the activation of G-protein coupled receptors, such the GLP-1 receptor in intestinal L-cells, and decrease T-cell activation and systemic inflammation. Patients with obesity, diabetics, and those with autoimmune diseases usually have a state of dysbiosis (abnormal biodome), which produces significant cravings for sugary and fatty foods, systemic inflammation and eventually cardiovascular disease. The balance of healthy vs. unhealthy gut bacteria is a modifiable risk factor, especially with high-fiber diets (vegetables, legumes and fruits), and represents a potential therapeutic target. Currently, biodome research is an active field that has provided great insight into the adverse effects of processed foods, various additives and chemicals in human disease.
For all these reasons, there is not a “one size fits all” approach to weight loss. Individualized, carefully selected strategies that include an in-depth assessment of each patient, then mapping out short-term realistic goals, represents a common-sense initial approach. Often other healthcare professionals such as a nutritionist, exercise physiotherapist and a psychologist or psychiatrist, are essential for successful weight loss. Accountability in adherence to the prescribed lifestyle, including dietary guidelines and regular physical activity that result in long-term behavior modification, constitute the more successful programs. Managing expectations, providing a positive mindset and encouragement are essential components of the patient-provider relationship.
In this modern era, with relatively new GLP-1and dual GLP-1/GIP agonists, administered once a week, and embraced by millions of people and celebrities worldwide, it is all too easy to fall into the trap of a weekly injection will resolve weight issues and other medical problems. Would new Nutrigenomics research focusing on the SNPs present in those who lose more than 15% to 20% of their weight versus those that fail to lose 5%, provide targeted information on who are the optimal candidates for such drugs? Can SNPs indicate who is more likely to maintain their weight loss for more than one or two years after drug discontinuation? Such information could be extremely useful to help us understand even more the relationships between biology and the environment. The reality now is that many, who do not meet the precise indications, are obtaining these medications from on-line pharmacies and other sources without medical supervision. This is far from ideal and will likely result in adverse consequences and outcomes. Currently in the U.S. the number of adults 20 years and older who are overweight and obese is approximately 75%, with all races affected and African American women as the most affected. The least overweight and obese are Asian populations, although these groups are catching up to the others. Given the current high monthly cost of these medications, lack of insurance coverage for many and the fact that on average 20-30%, as demonstrated in the clinical trials, will not be responders (lose less than 5% of their initial weight) or will stop the medication due to intolerability. Appropriate patient selection and education are paramount.
TREATMENT CONCLUSIONS AND RECOMMENDATIONS:
In addition to the above fundamental management concepts, the following are my personal opinions. As an internist and cardiologist with more than 30 years of experience in caring for overweight and obese diabetic and non-diabetic individuals, beyond lifestyle interventions, the following are my recommendations on prescribing a GLP-1 RA or GLP-1/GIP RA dual agent:
1-Primary Prevention (patients without established cardiovascular disease): Semaglutide and/or tirzepitide may be prescribed to obese non-diabetic patients at high-risk for cardiovascular disease to attain improvement in cardiometabolic parameters and weight loss (STEP trials and the semaglutide 13-study meta-analysis, SURPASS 1,2,3,4 and 5 trials, and SURMOUNT-1 and 4 trials). These patients were treated from 40 to 52 weeks with semaglutide and 88 weeks with tirzepatide. This should be the protocol in most outpatient clinics.
2-Secondary Prevention (patients with established cardiovascular disease): Consider using semaglutide at the doses in the published literature in obese type 2 diabetic adults with established cardiovascular and renal disease (SUSTAIN-6 TRIAL). Semaglutide may be used in obese non-diabetic adults with established cardiovascular disease (SELECT trial). These patients were treated for up to 104 weeks with semaglutide at a weekly dose of 0.5 mg-1.0 mg in SUSTAIN-6, and up to 39 months in SELECT with a weekly semaglutide dose of up to 2.4 mg.
3-Weight loss as an endpoint: Adults with and without type 2 diabetes with a BMI > 27 and at least one risk factor and those with a BMI > 30, in addition to intensive lifestyle intervention, including nutrition education, could be treated with one of the above agents for up to 6 months. Note that many of these patients may be pre-diabetic and are likely to benefit from these agents to prevent progression to full diabetes and improved cardiometabolic parameters. Individuals not responding after 3 to 6 months (less than 5% weight loss), compliant with the prescribed lifestyle and dose escalation to maximum trial levels (semaglutide 1.7 mg or 2.4 mg and tirzepatide 10 mg to 15 mg), should have the drug discontinued.
4-Non-responders and others with intolerability: In addition to intensive lifestyle interventions, these individuals may benefit from older FDA approved weight loss pharmacotherapy such as naltrexone-bupropion or phentermine-topiramate combinations for a period of up to a year. If available and affordable, as more research data emerges providing correlation between obesity and weight loss with high-BMI SNPs and those associated with successful diet induced weight loss, genetic risk testing could provide personalized data on the best strategy that may succeed in a particular individual. In time it would be ideal to have this tool as a point of service test in medical offices to best guide individual patients.
5-Patients responding to the GLP-1 or GLP-1/GIP agents who completed a treatment protocol as above and concerned about the very real phenomenon of regaining some or most of their weight, they can be switched to one of the older weight loss medications as above. In addition, a predominant plant-based diet with portion appropriate animal products, plenty of water, avoiding sugary beverages and meal replacement strategies without added sugars that contain plenty of protein and fiber. This strategy can create early satiety, optimize gut health and may be recommended to most patients.
6-Patients not covered by insurance: There are millions that may fit the above categories of patients but do not have access to the medications due to cost or lack of insurance coverage. Aside from intensive lifestyle intervention, a sponsored subsidized pool of each of the medications may be set up via a government-pharmaceutical partnership to allow qualified providers to enroll patients in the above program for up to 6 months depending on their individual characteristics. Perhaps patients could pay a much-reduced cost per month ($25 to $50), and they would need to participate in weekly 30-minute on-line tutorials with topics on obesity, diabetes and associated medical conditions. Patients would need to answer simple questionnaires each week to keep eligibility in the program. These tutorial courses and content could be prepared by experts in the field, approved and sponsored by the government-pharmaceutical partnership, and provided for free to participants. In addition, patients would need to tolerate the medication and lose at least 5% of their starting weight in the first 6 months to continue. Their provider would be responsible for approving participation beyond the initial 6 months, as long as the patient remains compliant with the prescribed lifestyle and successful tutorial completion.
7-Government-Private Sector Enterprises: The goal is to create healthier products for consumers. This following list is not all inclusive. Strategies could include the following:
(I)- Reverse Taxation Program (RTP): A proposal could be made to the food industry on a variety of products that would receive a tax credit as the sugar content and other additives are gradually decreased from year to year. These would include grocery store items and fast foods. Manufacturers and businesses becoming RTP compliant would be promoted via preferential marketing strategies that would increase exposure to consumers. Ultimately free market systems will reward RTP participants. A system could be devised whereby consumers purchasing RTP compliant products could get a tax credit each year. The more an individual purchases such foods and products, the greater the tax deduction. These credits could then be donated to charitable organizations whose core initiatives and mission are to improve community health, such as improving the quality of food in public school lunch programs.
(II)- Agricultural Subsidies: Government subsidies for crops and food products known to be harmful to health should be gradually stopped. Subsidies for vegetables, fruits and other healthy foods should be instituted, especially for organic products, and made affordable and readily available to at risk communities.
(III)- Food Industry-Medical Institutions and Agency Financial Relationships: Conflict of interest relationships should be disclosed and stopped. A soda company or cereal manufacturers or fast-food conglomerates should not be contributing money or sponsorships to various entities such as the American Heart Association or American Diabetic Association, in exchange for their endorsement or promotion as “healthy foods” or part of a “healthy diet”. To that effect, the original Swedish food pyramid from the early 1970s, with minor modifications, could once again serve to educate the population on healthy food choices.
Federico Maese MD
Internal Medicine/ Cardiology
April 2024.