By Edwin Davila, DO, MS, CISSN and Winona Gbedey

Innovation in Weight Management

By Edwin Davila, DO, MS, CISSN and Winona Gbedey

When engaging in conversations with patients regarding methods of preventing the progression of debilitating disease states, the topic of weight management often comes up. Weight loss has been proven to be protective against many life-altering and threatening morbidities. Heart disease, stroke, type 2 diabetes mellitus (T2DM) and several cancers, conditions that all have been linked to obesity, are among the leading causes of preventable, premature death in this country.

Across numerous fields of research investigating these chronic conditions, weight loss has continued to be a primary treatment modality. The 2017 ACC/AHA guidelines have championed weight loss as a core recommendation in combating hypertension. Investigations have identified a dose-response relationship with weight loss, producing approximately a one mmHg drop in systolic blood pressure for every kilogram of weight loss. This finding is significant, as a reduction of systolic blood pressure by 10 mmHg has been found to provide a relative risk reduction against the development of strokes and worsening heart failure by 26%. From this, we can see how weight loss can provide protection against significant life-altering events. Similarly, research conducted by Simons et. al, which was spurred by the need to find effective interventions against the rise in nonalcoholic fatty liver disease, identified obesity as the most significant modifiable risk factor for incidence of hepatocellular carcinoma and cirrhosis-related mortality. Their data strongly suggest that establishment of weight management and overall lifestyle modification could potentially prevent over 30,000 liver-related deaths in the U.S. each year. These are just a few examples of how weight loss and lifestyle modification are a keystone to the prevention of debilitating diseases.

Irrespective of the numerous benefits that weight management provides, we continue to see difficulties in combating the prevalence of obesity. Recent data from the CDC indicates the prevalence of obesity has reached an all-time high of 42.4%. The number of states in which at least 35% of its residents are classified as obese has nearly doubled since 2018. This puts the current total of states at 16, with Texas among them. In Bexar County, 65.7% of adults are classified as either overweight or obese, with high obesity rates disproportionally affecting communities of color.

With these growing numbers comes a need to identify new methods to assist our patients in battling obesity. A healthy diet and regular exercise are commonly touted as the mainstay of therapy for individuals struggling with weight loss; however, it is often difficult for patients to commit to these lifestyle modifications long-term. Current guidelines published by the National Institute of Diabetes and Digestive and Kidney Diseases recommend weight loss medications for individuals with a BMI over 27 with comorbidities, such as joint pain or metabolic syndrome, or who have a BMI over 30. These medications are not meant to replace lifestyle changes, but rather serve as an adjunct to help accelerate and facilitate the weight loss process. Orlistat (Xenical), phentermine-topiramate (Qsymia) and naltrexone-bupropion (Contrave) have served as the prototypical long-term weight loss drugs for many years. While several of these are still utilized, their long-term success has been variable.

A relative newcomer in our pharmacologic arsenal includes the GLP1 receptor agonists. Approved by the FDA in 2005, the first GLP-1 agonist – exenatide – has been incredibly effective for the treatment of T2DM. These agents work by activating GLP-1 receptors in the pancreas, which enhance the release of insulin and reduce the release of glucagon in response in hyperglycemic states. Through similar mechanisms in the nervous system and GI tract, they also reduce appetite, delay glucose absorption through delayed gastric emptying and increase satiety. Success in T2DM management has been noted in both the American College of Clinical Endocrinology and American Diabetes Association 2020 T2DM treatment guidelines, which recommend their use in combination with metformin, taking the place of the previously recommended thiazolidinediones and sulfonylureas. Continued research into this class has shined a light on the extent to which GLP-1 agonists have been shown to exert their effects throughout the body. Research has found GLP-1 receptors in the myocardium, vascular wall, adipocytes, enterocytes of the GI system − even in the brain. With these numerous mechanisms, one effect that has generated significant intrigue has been the notable weight loss patients utilizing GLP-1s have experienced.

While promising, these weight loss effects were seen in patients who were both overweight and had T2DM. The STEP Trial was designed to see if similar results would be seen irrespective of T2DM. First published in the March 2021 edition of the New England Journal of Medicine using the GLP-1 agonist Semaglitide, the STEP trial recruited approximately 2000 volunteers with a BMI of 30 or greater and without diabetes, or a BMI of 27 or greater with one or more treated or un-

treated coexisting condition. Participants were randomly assigned to receive once weekly Semaglitide titrated to 2.4mg or placebo. Both groups were followed for 68 weeks and provided lifestyle interventions that promoted physical activity and healthy food choices. At week 68, the group that received Semaglitide achieved an average weight loss of 15% of overall body mass while the placebo group only saw a 2.4% weight reduction. These findings were quite impressive, as the weight loss achieved with Semaglitide was 1.5 to two times greater than those averaged by the current medications on the market. Additionally, 1/3 of the participants lost at least 20% or more of overall body mass. It is no surprise that shortly after the publications of these findings, the FDA approved Semaglitide for the treatment of adults with obesity. While this approval is still very recent, coming in June 4, 2021, it has generated significant hope as a new tool for the treatment of obesity.

Further advancements were seen with the SURMOUNT-1 trial published in the July 2022 edition of the New England Journal of Medicine which continued to show the potential of these new class of agents showcasing the impact of Tirzepatide, a dual GLP-1 agonist and glucose-dependent insulinotropic polypeptide (GIP) agonist. In this international, placebo controlled, double blind, randomized controlled trial 2539 adults with BMI requirements similar to the STEP-1 trial were followed for 72 weeks. Participants were equally distributed into 4 groups, one placebo and three receiving Tirzepatide at different dosages. Results were quite significant with approximately 90% of participants achieving a 5% loss in overall body mass and 30% of participants losing 25% of body mass or more. While this trial is still fairly new, it highlights the growing interest in these novel agents and the potential they have in the treatment of obesity.

As we continue to investigate new methods for the treatment of obesity, we must also continue to advance our own understanding of the disease itself and the message we hope to convey to our patients. Our approach must be focused on treating obesity as a chronic condition and not minimizing it to simply a battle of will power. Research shows that obesity is characterized by disruption in weight-regulating hormones, such as leptin, ghrelin and GIP, that hinders weight loss and drives weight regain. Thus, obesity is not a one-dimensional issue that can be solved by simply eating less and doing more. Instead, it is multifactorial: encompassing the patient’s environment, disparities in food access and learned behaviors rooted over decades. Treatment of obesity should mimic this change in thinking. Just as anti-hypertensives are used long-term for the management of high blood pressure, so too must anti-obesity medications be used chronically in the fight against obesity. We hope the GLP-1 & GIP agonists will fill this role as they continue to pioneer a new wave in weight management therapy.

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Edwin Davila, DO, MS, CISSN is a resident physician specializing in internal medicine at the Texas Institute of Graduate Medical Education and Research. Dr. Davila is a member of the Bexar County Medical Society.

Winona Gbedey is a medical student at the UT Health San Antonio Long School of Medicine and a member of the BCMS Publications Committee.