The Dark Side of the Miracle Drug Tirzepatide


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Based on the successful completion of several clinical trials with weight loss drugs, including the new class of GLP-1 agonists, current treatment guidelines for obesity recommend anti-obesity medications in addition to diet and lifestyle modifications to promote weight reduction, facilitate weight maintenance, and improve health outcomes in people with obesity.

“In other words, these treatments deal solely with the symptoms, not the causes of obesity.”

Randomized withdrawal studies of anti-obesity medications and weight loss surgeries to date, have consistently demonstrated clinically significant body weight regain with cessation of therapy. In other words, these treatments deal solely with the symptoms, not the causes of obesity. To determine the need for continued treatment with tirzepatide, following successful weight loss to maintain the achieved weight loss, investigators of the SURMOUNT-4 study investigated the effect of continued treatment with the maximum tolerated dose (i.e., 10 or 15 mg) of once-weekly tirzepatide, combined with diet and physical activity, and compared the results with placebo, in participants with obesity or in the overweight category.

In a randomized withdrawal study, all participants are taking the active drug and after significant weight loss are then randomly assigned to either continue taking the active drug or to getting a placebo. Such a design is used by investigators to demonstrate the need for continued drug use to prevent new weight gain. The main results of the large randomized controlled trial to achieve weight loss were published in 2022 in the New England Journal of Medicine, and have resulted in the recent FDA approval of Zepbound for the treatment of obesity. I wrote about this in a previous post.

“…participants …who completed the 36-week period experienced a remarkable mean weight reduction of 20.9%.”

The results of the randomized withdrawal of Tirzepatide of this phase 3 clinical trial were recently published by J. Aronne and coauthors in the Journal of the American Medical Association. Study participants were obese adults with a BMI greater than or equal to 30, or greater than or equal to 27 and a weight-related complication, excluding diabetes. The trial was conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period (where participants knew they were on the medication) followed by a double-blind, placebo-controlled period which included 335 participants that received the drug and 335 that received a placebo. During the open label lead in period, participants (n = 670; mean age, 48 years; 71% women; mean weight, 107.3 kg who completed the 36-week period experienced a remarkable mean weight reduction of 20.9%.

The study then aimed to see what happened with the achieved weight loss when participants stopped taking the medication (placebo group), or when they continued taking the drug at a maximal tolerated dose of 15 or 20 mg/week.

“…withdrawing tirzepatide after successful weight loss led to substantial regain of most of the lost weight…”

Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss achieved during the lead-in period compared with 16.6% receiving placebo (P < .001). The overall mean weight reduction from week 0 to 88 was 25.3%for tirzepatide and 9.9% for placebo, clearly demonstrating the need for continued treatment. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide than with placebo. The authors concluded from their findings that in participants with obesity or overweight, withdrawing tirzepatide after successful weight loss led to substantial regain of most of the lost weight, whereas continued treatment maintained and augmented initial weight reduction.

There is no question that the success of this drug in achieving a substantial weight loss is remarkable, comparable to the weight loss achieved with the invasive surgical interventions changing the anatomy of the upper gastrointestinal tract.

“Far from being a cure for the raging epidemic of non-transmissible chronic diseases related to obesity …it is just another super expensive band aid…”

However, there is a worrisome side to this success story, which has been illustrated by the results of the SURMOUNT-4 analyses, but is hardly being addressed in the media. Far from being a cure for the raging epidemic of non-transmissible chronic diseases related to obesity and associated metabolic disorders, it is just another super expensive band aid, that will primarily benefit the profits of the pharmaceutical industrial complex. These new weight loss drugs are in line with blood pressure medications and the statin drugs for hyperlipidemias (statins), all of which share the need for lifelong therapy. For the majority of patients who can afford this expensive medication, it will decrease the risk for developing the well-known medical complication of obesity and metabolic syndrome without the need for difficult lifestyle modifications and without the need of politicians to address the societal and economic root causes of the problem.

With the exception of some highly motivated and strong-willed individuals who will be able to maintain their healthy weight after losing the extra pounds with a 3-months course of Zepbound, what percentage of people will be able or willing to dramatically change their lifestyles with vigorous daily exercise and a change of their dietary habits from the standard American diet to a Mediterranean-type diet concept? What percentage of the population (in particular those in the lower socioeconomic segments of society, who are most affected by the obesity and chronic disease epidemic) will be able to afford a medication which currently costs more than $1000 a month?

“Obesity is a systems biological disorder, which cannot be cured with a magic pill.”

The biological mechanisms that have evolved over millions of years to maintain a stable body weight despite fluctuations in food availability during human history, have not been able to deal with the worldwide adoption of the standard American diet and with the dramatic lifestyle changes that have occurred during the past 75 years. As explained in detail in my latest book, The Mind Gut Immune Connection, our current chronic disease epidemic is propagated by the agricultural and food industrial complex and maintained by their powerful lobby, producing and aggressively marketing inexpensive, unhealthy, ultra-processed foods which disproportionally affects Americans on the lower socioeconomic segment of society. Should medical insurance companies be forced to cover these expensive new drugs? Once the public pressure builds to make these drugs available to 40% of Americans who would benefit, the medical system has to put mechanisms into place that make access to these drugs contingent on meaningful changes in lifestyle and diet starting in childhood.

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.