Weight loss with tirzepatide was fairly uniform across different body mass index (BMI) ranges, ages, and number of obesity-related comorbidities in patients with overweight/obesity without type 2 diabetes.

These were the main findings in a session about tirzepatide — the dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) agonist — for obesity, presented at ObesityWeek^®.

In May, tirzepatide (Mounjaro), a once-weekly subcutaneous injection, was approved by the US Food and Drug Administration for glycemic control in patients with type 2 diabetes based on the SURPASS clinical trials.

Then in June, at the American Diabetes Association 2022 annual meeting, researchers reported “unprecedented” weight loss with tirzepatide in patients without type 2 diabetes, in the phase 3 SURMOUNT-1 clinical trial.

A month ago (October 6), the US Food and Drug Administration (FDA) granted fast track status (expedited review) to tirzepatide for use as an anti-obesity drug.

Now these new analyses from SURMOUNT-1 show that “regardless of BMI, regardless of age, regardless of number of obesity-related complications, there was a clear dose-related weight loss that was pretty consistent across groups,” Session Chair Patrick M. O’Neil, PhD, who was not involved with this research, summarized.

“The absolute levels of these weight losses are higher than we’ve seen thus far with [anti-obesity] medications,” O’Neil, who is professor of psychiatry and behavioral sciences and director of the Weight Management Center at the Medical University of South Carolina, in Charleston, added.

“Semaglutide took things up one big notch, and this is up a little notch above that,” he told Medscape Medical News in an interview.

“I’m a psychologist. It should be remembered that in all cases, the FDA approvals are predicated to using [drugs] as an adjunct to diet and exercise change as well,” he stressed.

“I don’t think people should expect that any medication that is currently available will have a lasting effect when it’s no longer taken,” he continued.

“We don’t expect any of these [anti-obesity] medications to be making any permanent physiological changes,” O’Neil added, but patients could “use this medication to help themselves make some long-lasting behavioral changes, so that when they come off the medication, hopefully they’ll be able to continue these new patterns.”

“Clearly the medications are having a significant impact,” he emphasized.

BMI, Age, Comorbidity Subgroups, and Overall QoL in SURMOUNT-1

SURMOUNT-1 compared the efficacy and safety of tirzepatide 5, 10, and 15 mg subcutaneous once-weekly to placebo, as an adjunct to a reduced-calorie diet and increased physical activity. The study included 2539 adults without type 2 diabetes who had obesity (BMI ≥ 30 kg/m²) or overweight (BMI ≥ 27 kg/m²) with at least one obesity-related complication (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease).

Age Subgroups

Robert F. Kushner, MD, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, noted that “Excessive lean mass loss is a clinical concern in elderly individuals being treated for obesity,” so it’s important to know if weight loss with tirzepatide differs by age.

The researchers performed a post-hoc analysis in patients who had dual-energy X-ray absorptiometry (DXA) readings at baseline and week 72 (oral abstract 109).

The three age groups in the current analysis were < 50 years old (99 patients), ≥ 50 to < 65 years old (41 patients), and ≥ 65 years old (20 patients). Overall, 63% of patients were age < 50 years, 31% were age 50 to < 65 years, and 6% were ≥ 65 years.

At 72 weeks, patients taking 5, 10, and 15 mg/week tirzepatide lost 21.5%, 20.8%, and 22% of their initial body weight, respectively.

“Tirzepatide significantly lowered total body mass versus placebo regardless of age subgroups,” and it “consistently lowered fat mass, lean mass, fat-mass-to-lean-mass ratio, and visceral fat mass across age subgroups,” Kushner reported.

BMI Subgroups

Louis J. Aronne, MD, Weill Cornell Medical College, New York City, presented findings from a prespecified analysis of BMI subgroups (oral abstract 110).

The four BMI subgroups were:

• ≥ 27 to < 30 kg/m² (overweight), mean initial weight 178 pounds, mean weight reduction 29 to 30 pounds

• ≥ 30 to < 35 kg/m² (class 1 obesity), mean initial weight 198 pounds, mean weight reduction 33 to 43 pounds

• 35 to < 40 kg/m² (class 2 obesity), mean initial weight 228 pounds, mean reduction 34 to 56 pounds

• 40 kg/m² (class 3 obesity), mean initial weight 280 pounds, mean weight reduction 44 to 64 pounds

Patients with an initial BMI of ≥ 35 to < 40 kg/m² who received the 15 mg/week dose of tirzepatide had the greatest weight loss, at 24.5%, which is approximately what is seen with bariatric surgeries such as sleeve gastrectomy (25%).

The proportion of patients reaching ≥ 5% weight reduction was approximately 90% in all weight categories. “These numbers are unprecedented,” said Aronne.

In addition, overall, 73% to 90% of patients receiving the 5 to 15 mg doses of tirzepatide achieved ≥ 10% body weight reduction, and “something we never thought we would see” is that 50% to 78% of the patients receiving the drug lost 15% or more of their body weight.

In reply to an audience question, Aronne said it would take further study to determine who would respond well to tirzepatide.

And in reply to another question about whether it would make sense to treat to a target of a normal BMI, he said: “I think we are getting there.”

Patients in the 27 to 30 kg/m² BMI category lost about the same amount of weight at a 5-mg dose as at a higher dose, suggesting they should stick to the lower dose, which would likely also have fewer side effects, he noted.

Number of Comorbidities

Comorbidities in SURMOUNT-1 included hypertension, dyslipidemia, obstructive sleep apnea, atherosclerotic cardiovascular disease, osteoarthritis, anxiety/depression, polycystic ovary syndrome, non-alcoholic fatty liver disease, and asthma/chronic obstructive pulmonary disease. Of the patients with no comorbidities, 32.6% had prediabetes (oral abstract 111).

Sriram Machineni, MD, University of North Carolina, Chapel Hill, noted that obesity is associated with a significantly increased risk of clustering of ≥ 2 obesity-related complications, but little is known about how this affects outcomes. 

The patients in SURMOUNT-1 were classified into three groups based on number of comorbidities:

• 0 comorbidities, 37% of patients: baseline mean age of 39, mean duration of obesity of 12 years, 29% men

• 1 comorbidity, 27% of patients: baseline mean age of 44, mean duration of obesity of 14 years, 31% men

• 2 or more comorbidities, 36% of patients: baseline mean age of 52, duration of obesity 17 years, 37% men

Regardless of the number of comorbidities, all doses of tirzepatide resulted in a greater reduction in body weight compared with placebo.

Quality of Life

Jiat Ling Poon, MD, an employee of Eli Lilly, presented findings from patient-reported replies to questionnaires including Impact of Weight on Quality of Life-Lite (IWQOL-Lite), which assesses physical and psychosocial health, and the Short Form-36 Health Survey, which assesses physical functioning, bodily pain, vitality, role-emotional, role-physical, general health, social functioning, and mental health (oral abstract 112).

Tirzepatide at all doses resulted in significantly greater improvements in patient-reported outcomes compared with placebo.

Meanwhile, the phase 3 SURMOUNT-2 clinical trial of tirzepatide for weight loss in patients with type 2 diabetes is projected to be completed in April 2023.  

The studies were funded by Eli Lilly.

ObesityWeek^® 2022. Oral abstracts 107-112. Presented November 4, 2022.

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