Could This New Weight Loss Drug Become the Best-Selling Drug of All-Time?


Please login to view this content , or sign up for an account

Obesity is a chronic disease that results in substantial global morbidity and mortality. According to the CDC, 40% of Americans are obese, and 32% are overweight. Soaring obesity rates make the United States the fattest country within The Organization for Economic Co-Operation and Development (OECD), a group made up of 38 countries in Europe, Asia and South America. Overweight and obesity rates have increased steadily since the 1980s in both men and women, and three out of four people are projected by the OECD to be overweight or obese within 10 years. Obesity is part of the worldwide epidemic of chronic, non-communicable diseases, which also includes metabolic syndrome, type-II diabetes, cardiovascular diseases, neurodegenerative diseases and liver disease.

Historically, the treatment of obesity focused almost exclusively on lifestyle-based approaches, including calorie restriction and different types of diets. However, evidence that diet and exercise prompt physiological counterregulatory mechanisms that limit weight reduction and impede weight maintenance has led to the realization that obesity is a complex, multi-component metabolic disease of energy homeostasis involving multiple dysregulations within the brain-gut-microbiome system.

“…endocrine cells sandwiched between the cells lining our gut…”

After many disappointing attempts to develop effective anti-obesity treatments, the pharmaceutical industry has finally come up with a new class of highly effective medications, the glucagon-like peptide-1 (GLP-1) receptor agonists. Studies with long-acting GLP-1 receptor agonists have demonstrated that greater efficacy with acceptable safety could be achieved by targeting the pathways of endogenous nutrient-stimulated hormones, so-called incretins. Amongst many other effects on the complex system of appetite and satiety regulation, incretins are released from endocrine cells sandwiched between the cells lining our gut in response to food components and to metabolites produced by gut microbes.

“…may lower the risk of heart disease, such as heart failure, stroke and kidney disease.”

A group of seven FDA-approved and currently marketed GLP-1 receptor agonists with trade names such as Wegovy, Ozempic and Mounjaro, were found to result not only in blood sugar control, but also in significant and sustained weight loss and improvements in several other diseases of the chronic health epidemic. Recent research shows that some drugs in these groups may lower the risk of heart disease, such as heart failure, stroke and kidney disease.

Glucose-dependent insulinotropic polypeptide (GIP), is another nutrient-stimulated hormone secreted by endocrine cells in the gut in response to fat, protein and some sugars entering our system. GIP regulates appetite and energy balance through cell surface receptor signaling in the brain and adipose tissue. One of these molecules, which combines both GIP and GLP receptor agonism theoretically would be expected to lead to greater efficacy in weight reduction, than a GLP-1 receptor agonist alone. Both agonists stimulate receptors in the hypothalamus to increase satiety after a meal and function as so-called incretins, which are molecules that stimulate hormone release from the pancreas and play a crucial role in blood sugar control (insulin and glucagon). To test this hypothesis, an international group of investigators and members of the pharmaceutical company, Eli Lilly (which developed the drug), performed a large randomized controlled trial and published the results in the New England Journal of Medicine in July 2022, with lead author Ania M. Jastreboff. The study aimed to test the efficacy and safety of tirzepatide (trade name Zepbound) for weight loss. The identical molecule, under the name of Mounjaro had already obtained FDA approval for the treatment of type II diabetes, and had been used off-label by many patients for weight loss.

In this phase 3 double-blind, randomized controlled trial, the investigators assigned 2539 adults with a body-mass index of 30+ (or 27+ and at least one weight-related complication, excluding diabetes) to receive once-weekly, subcutaneous tirzepatide in three different doses (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks. Participants in all groups were on a reduced caloric intake diet and lifestyle intervention. Primary end points of the study were the percentage change in weight from baseline and a weight reduction of 5% or more.

“…mean percentage change in weight at week 72 was 21%…”

At baseline, the mean body weight of the study groups was 104.8 kg, the mean BMI was 38.0, and 94.5% of participants had a BMI of 30 or higher. The highly significant mean percentage change in weight at week 72 was 21% with 15-mg doses, compared to −3.1% with placebo. The percentage of participants who had weight reduction of 5% or more was 91% with 15 mg of tirzepatide, respectively, and 35% (95% CI, 30 to 39) with placebo. 57% of participants in the 15 mg group had a reduction in body weight of 20% or more, as compared with 3% in the placebo group. In addition to the significant weight loss, improvements in all cardiometabolic measures, including blood pressure, fasting insulin levels and blood lipids were observed with tirzepatide, including a conversion of a pre-diabetic state to normoglycemia (normal blood glucose). The most common adverse events with tirzepatide were gastrointestinal, and most were mild to moderate in severity, occurring primarily during dose escalation. Zepbound led to an average weight loss of 22.5% body weight, or about 52 pounds, surpassing all currently available weight loss medications on the market.

Based on these impressive results, the drug Zepbound recently obtained FDA approval as a weight loss drug, and according to Eli Lilly, will be available in the US by the end of the year. Even though this obesity treatment comes at a whopping cost of more than $1,000 a month, some analysts predict the weekly injectable medication could become the best-selling drug of all time.

Is this “miracle drug” a good or a bad thing for patients and the US healthcare system?

Many physicians will celebrate this drug as the long-awaited solution to the growing burden of the epidemic of chronic non-transmissible diseases, which I have discussed extensively in my book The Mind Gut Immune Connection. For many patients, drugs like Zepbound will be the quick fix for their growing weight loss problems and deteriorating metabolic health, bypassing challenging lifestyle and diet changes. For the pharmaceutical industry, it is the second major big win after the statin revolution, which has resulted in a situation that a great majority of patients over 65 years of age are now on for life.

“…ongoing and worsening chronic disease epidemic affecting younger and younger populations.”

The problem is the fact that the cost of these new weight loss drugs has the potential to bankrupt the already strained healthcare systems in the US, and countries around the world. Furthermore, the fact that this weight loss approach is not a temporary expense, but requires lifelong therapy, will make the financial burden particularly severe. A discontinuation of the drug without implementing serious dietary and lifestyle changes will result in the well-known yo-yo effect, which leads to body weight increases to values even higher than when the medication was first started. And most of all, this class of weight loss drugs, just like statins, have no beneficial effect on the root cause of the ongoing and worsening chronic disease epidemic affecting younger and younger populations.

The paradox of this situation is that while the pharmaceutical industry is coming up with more effective (and expensive) therapies to deal with the consequences of our unhealthy modern lifestyles, to keep patients alive, but preventing them from dying from the complications, the same success will distract the world from solving the big underlying problems that have led to the current chronic disease epidemic: by addressing lifestyle, diet, food production and the marketing of unhealthy food choices.

Emeran Mayer, MD is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA, the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience and the Founding Director of the Goodman-Luskin Microbiome Center at UCLA.