The New Wave of Weight Loss

Blending pharmaceuticals, nutraceuticals and integrative approaches for safe, sustainable weight loss that works.

Of all the challenges encountered by practitioners, helping patients achieve and maintain weight loss continues to be one of the most frustrating, futile issues. Now, a new generation of prescription drugs offer hope, but not without significant complications. Meanwhile, novel nutraceuticals promise a safe, natural solution to pharmaceuticals—and provide opportunities for practitioners to craft integrative, personalized protocols that enhance patient outcomes, minimize failures and encourage long-term weight-loss success.

The magnitude of the problem cannot be overemphasized. According to the latest data, about 42 percent of U.S. adults are obese, a notable rise since 1999. Childhood obesity statistics are especially troubling: for children and adolescents aged 2 to 19, the prevalence of obesity reached almost 20 percent. Along with obesity-related conditions like heart disease, stroke and some cancers, mental health disorders are significantly correlated with body weight: 43 percent of adults with depression were obese, and studies point to a complex bidirectional relationship, in which obesity increases risk of depression and depression increases risk of obesity. And being overweight or obese is associated with premature death: the risk is higher with each additional pound, and being obese is likely to hasten mortality by more than nine years.^{1, 2, 3, 4, 5}

Despite these alarming statistics and implications, long-term weight loss remains one of the most difficult issues for patients and practitioners. Why is losing weight, and keeping it off, so hard?

“If I had the answer to that, I would write a book—or maybe win a Nobel Prize,” says Jacqueline Jacques, ND, FTOS, Naturopathic Doctor & Fellow of the Obesity Society. “It’s certainly multifactorial, tied closely to biological wiring that’s linked to survival of our species, so that storing energy is much easier than losing it. Easy availability of calories in the environment is another part of the puzzle, and clearly other environmental and epigenetic factors are also at play. In short: it’s complicated.”

A shift in perspective is required, since the traditional approach—eat less, exercise more—clearly isn’t working. “The human body is built to fight back against weight loss,” says Gabriela Bantas, Technical and Science Advisor at Calocurb. “Reducing caloric intake by 25 percent doubles the sensation of hunger within four months, driven by increased levels of ghrelin and the body’s effort to maintain homeostasis.” In a primal survival mechanism, humans are generally wired to gain weight and store calories, so caloric restriction will always, to some degree, be viewed physiologically as potential starvation.⁶

“The body responds by lowering metabolic rate, making weight loss even harder,” says Jacques. “With each subsequent attempt to lose weight, it will lower metabolic rate even more. It can get to a point where people either must be eating very little food (which is nutritionally a terrible idea) or exercising hours each day. That’s not sustainable.” Continued caloric restriction further inhibits metabolic rate and degrades lean mass, creating a repetitive pattern that’s doomed to fail.

This isn’t new information: in one meta-analysis of 29 weight loss studies, over half of the lost weight was regained within two years, and by five years, more than 80 percent of lost weight was regained. Even worse, another meta-analysis showed that one-third to two-thirds of dieters ended up at a higher weight than before. Only 20 percent of subjects undergoing weight-loss programs achieve a degree of long-term success, and 53 percent cheat on diets because they’re hungry.^{7, 8, 9, 10, 11}

That’s one reason recently developed medications that minimize cravings, suppress appetite and lead to meaningful weight loss are so popular—and important for both patients and practitioners. “These drugs are not in opposition to integrative health but are instead an opportunity to create tailored regimens for patients taking GLPs,” says Jacques. “By allowing for weight loss to be less of a struggle for people in the most serious classes of overweight and obesity, they can now experience much greater benefits for other areas of health that many have taken a backseat to weight, including everything from joint health to immune health to gut health.”

 

The new wave of weight loss: pharmaceuticals, nutraceuticals and integrative solutions.

The checkered history of anti-obesity medications has made practitioners and patients alike understandably cautious and concerned. While earlier generation drugs like Sibutramine and Rimonabant were effective, they were also fraught with significant problems. Many were eventually pulled from the market after evidence of serious adverse effects, including increased rates of cardiovascular events, heart attack and stroke, and psychiatric effects such as mood changes, depression, anxiety and suicidal thoughts.

The introduction of semaglutide medications like Wegovy and Ozempic changed the playing field. Used for diabetes control since 2014, these GLP-1 receptor agonists were approved in the United States for weight loss in 2021. They work by injecting a synthetic version of the GLP-1 hormone, the main natural satiety hormone released by enteroendocrine cells in the small intestine after eating.”GLP-1 regulates appetite and provides a connection between the gut and the brain to indicate satiety,” says Bantas. “ Specifically a GLP-1 agonist elevates insulin secretion and inhibits glucagon secretion to lower blood glucose, suppressing appetite, increasing satiety, delaying gastric emptying and promoting weight loss.”

On the upside, they’re highly effective, offering rapid and substantial reductions in weight—and hope to their users. Initial research shows a 15 to 17 percent weight loss over a 68-week treatment, more than double what’s typically see on weight-loss medications.^{12, 13}

“Do they work? Absolutely,” says Edward Walker, PhD, researcher at The New Zealand Institute for Plant and Food Research, University of Auckland, NZ. “But what happens with you go off these medications?” Studies suggest most patients regain the weight they lost after halting semaglutide, and in one trial examining short-term use of Wegovy, half the participants who stopped the medication regained 70 percent of their weight after 48 weeks.¹⁴

It appears semaglutide drugs must be used indefinitely—and that’s a problem. Gastrointestinal complaints like nausea, vomiting, diarrhea, constipation and abdominal distress affect more than 30 percent of users. Other adverse effects include hypoglycemia, dizziness, headache, rapid heartbeat, irritability and gallbladder disease, with preliminary research suggesting a potentially increased risk of kidney damage, thyroid tumors and pancreatic cancer. Additionally, the speedy weight loss characteristic of these medications means patients are losing lean mass, both muscle and bone, impairing metabolism and making long-term weight maintenance that much harder. And they’re very expensive: with out-of-pocket prices averaging $1000 to $1500 a month, they’re unaffordable for most people.

“This really highlights an issue we have with weight management in general,” says Walker. “Obesity is a chronic disease. If you have someone that’s obese or overweight, they require lifelong management to achieve and maintain a healthy body weight.”

That doesn’t mean semaglutide can’t be part of a comprehensive, GLP-1 adjacent strategy that blends functional medicine and nutrition with prescription drugs. “Some people may need combinations of different weight loss approaches, or need them sequentially,” says Jacques. “I would generally be looking at adjusting protein intake to prevent muscle loss, supplementing to avoid nutrient gaps, supporting bone health and optimizing metabolic function and the microbiome. Helping them engage in some form of physical activity that they can be consistent with over time is crucial. Most important, make sure patients see their practitioner as an ally who will be there to help them if their weight loss stalls or if they start to regain.”

A skillfully designed supplement regimen is vital since nutrient shortfalls can indirectly contribute to weight gain or hinder weight loss efforts. Magnesium deficiency impairs the body’s ability to use glucose effectively, and one review showed magnesium supplementation led to decreases in BMI, as well as reduced weight and waist circumference for some groups. B-vitamin deficiencies impact metabolism, energy production and appetite regulation. Vitamin D influences lipolysis and lipid synthesis, improves insulin signaling pathways and decreases adipose tissue inflammation, and low levels are linked with higher risk of obesity. Iron is involved in thyroid hormone synthesis, and the omega-3 fatty acids EPA and DHA play a role in insulin sensitivity and appetite regulation. Other supplements may directly promote weight loss through a variety of mechanisms, such as blunting hunger, enhancing carbohydrate metabolism, increasing thermogenesis and boosting fat-burning. But high-quality studies are sparse, with limited proof of efficacy and few human clinical trials.^{15, 16, 17, 18, 19}

New, evidence-based nutraceuticals that mirror the actions of semaglutide may offer a safe, sustainable substitute for prescription weight-loss medications. One patented, natural GLP-1 activating ingredient called Amarasate^® has been shown in human trials to influence the body’s appetite-regulating mechanism, safely and effectively. Extracted from a specific cultivar of New Zealand-grown hops, Amarasate works by stimulating bitter-sensing type 2 receptors (TAS2Rs) in the small intestine and triggering the release of appetite-suppressing hormones GLP-1, CCK and PYY.

Research into this novel ingredient was initiated in 2010, with a $20 million grant funded by the New Zealand government to develop a gut-targeted, plant-based nutraceutical for appetite control. The hypothesis: bitter taste receptors are present in the gut, based on historical evidence of the appetite-modulating effects of bitter compounds.

In the first hospital-based study, gut biopsies from 28 volunteers demonstrated the presence of TAS2Rs throughout the gut. “Using an in-vitro gut cell model containing appetite-suppressing gut hormones,” says Bantas, “a thousand different plant extracts, compounds and pharmaceuticals were tested to see if they could prompt these cells to release appetite-suppressing hormones following activation of TAS2Rs.” According to Bantas, Amarasate^® was the only plant extract shown to elicit a marked physiological response.

“Amarasate^® passes down the intestinal tract, stimulating the gastrointestinal bitter taste receptors,” says Walker. “It takes effect within one hour, increasing GLP-1, CCK and PYY six times above baseline and twice the normal post-prandial release of gastric hormones over four hours, following the body’s endogenous hormonal release cycle.” Unlike semaglutide injectables, which elevate GLP-1 levels to supra-physiological concentrations, resist breakdown and impact natural rhythms, the ingredient doesn’t interfere with harmonious, balanced gut and brain appetite functions.

Three human clinical trials found Amarasate^® effectively controls appetite by triggering endogenous GLP-1, CCK and PYY, reducing feelings of hunger by 30 percent, cravings by up to 40 percent and caloric intake on average by 18 percent.^{20, 21} Additionally, studies demonstrate limited absorption of Amarasate^®, with 99 percent being degraded in the lower intestine, minimizing the risk of interactions with other medications. The ingredient is broken down in 24 hours, so it can be used intermittently without having to titrate dosages up or down. Because adverse reactions are minor and infrequent, Amarasate^® may prove to be a safe, affordable alternative to prescription weight-loss drugs—and can play a key role in an integrative weight-management protocol.

 

References:

1. Overweight and Obesity Statistics, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, September 2022.
2. Overweight and Obesity Data and Statistics, Centers for Disease Control and Prevention, 17 May 2022.
3. Luppino FS et al. Overweight, obesity, and depression: A systematic review and meta-analysis of longitudinal studies. Arch Gen Psychiatry, 2010; 67(3):220–9.
4. Greenberg JA. Obesity and early mortality in the United States. Obesity (Silver Spring). 2013 Feb;21(2):405-12.
5. Global BMI Mortality Collaboration, Di Angelantonio E et al. Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. Lancet. 2016 Aug 20;388(10046):776-86.
6. Makris MC et al. Ghrelin and Obesity: Identifying Gaps and Dispelling Myths. A Reappraisal. In Vivo. 2017 Nov-Dec;31(6):1047-1050.
7. Anderson JW et al. Long-term weight-loss maintenance: a meta-analysis of US studies. Am J Clin Nutr. 2001 Nov;74(5):579-84.
8. Mann T et al. Medicare’s search for effective obesity treatments: diets are not the answer. Am Psychol. 2007 Apr;62(3):220-33.
9. Hall KD, Kahan S. Maintenance of Lost Weight and Long-Term Management of Obesity. Med Clin North Am. 2018 Jan;102(1):183-197.
10. Rössner S et al. Long-term weight loss and weight-loss maintenance strategies. Obes Rev. 2008 Nov;9(6):624-30.
11. Mela DJ. Novel food technologies: enhancing appetite control in liquid meal replacers. Obesity (Silver Spring). 2006 Jul;14 Suppl 4:179S-181S.
12. Gao X et al. Efficacy and safety of semaglutide on weight loss in obese or overweight patients without diabetes: A systematic review and meta-analysis of randomized controlled trials. Front Pharmacol. 2022 Sep 14;13:935823
13. Polidori D et al. How Strongly Does Appetite Counter Weight Loss? Quantification of the Feedback Control of Human Energy Intake. Obesity (Silver Spring). 2016 Nov;24(11):2289-2295.
14. Wilding JPH et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab. 2022 Aug;24(8):1553-1564.
15. Askari M et al. The effects of magnesium supplementation on obesity measures in adults: a systematic review and dose-response meta-analysis of randomized controlled trials. Crit Rev Food Sci Nutr. 2021;61(17):2921-2937.
16. Oliai Araghi S et al. B-vitamins and body composition: integrating observational and experimental evidence from the B-PROOF study. Eur J Nutr. 2020 Apr;59(3):1253-1262.
17. Pesta DH, Samuel VT. A high-protein diet for reducing body fat: mechanisms and possible caveats. Nutr Metab (Lond). 2014 Nov 19;11(1):53.
18. Manore MM, Patton-Lopez M. Should Clinicians Ever Recommend Supplements to Patients Trying to Lose Weight? AMA J Ethics. 2022 May 1;24(5):E345-352.
19. Watanabe M et al. Current Evidence to Propose Different Food Supplements for Weight Loss: A Comprehensive Review. Nutrients. 2020 Sep 20;12(9):2873.
20. Walker EG et al. An extract of hops (Humulus lupulus L.) modulates gut peptide hormone secretion and reduces energy intake in healthy-weight men: a randomized, crossover clinical trial. Am J Clin Nutr. 2022 Mar 4;115(3):925-940.
21. Walker E et al. Gastrointestinal Delivery of Bitter Hops Extract Reduces Appetite and Food Cravings in Healthy Adult Women Undergoing Acute Fasting. Preprints 2023, 2023090416.