Zepbound’s Weight Loss, Cardiometabolic Benefits Hold Up at 3 Years

SAN ANTONIO — Patients with overweight or obesity lost an average one-fifth of their body weight with the highest dose of tirzepatide (Zepbound) and maintained that loss for more than 3 years, follow-up of a randomized trial showed.

And patients taking any dose of the dual GLP-1/GIP receptor agonist had improvements in blood glucose, lipids, blood pressure, and quality-of-life measures, according to 3-year outcomes data of SURMOUNT-1 presented at the ObesityWeek annual meeting.

Over 176 weeks, participants taking 15 mg of tirzepatide lost an average 22.9% of their body weight, compared with 19.9% with 10 mg, 15.4% with 5 mg, and 2.1% with placebo (P<0.001), reported Ania Jastreboff, MD, PhD, of the Yale Obesity Research Center at Yale University School of Medicine in New Haven, Connecticut. Tirzepatide participants’ average weight reduction ranged from 34.6-54.2 pounds.

“Participants who received tirzepatide reported greater improvements in all domains of health-related quality of life compared to those who received placebo,” Jastreboff said. These domains included physical functioning, bodily pain, general health perception, vitality, social functioning, emotional role functioning, and mental health. But when patients went off tirzepatide for 4 months at the end of the trial, they experienced weight regain and a shift toward baseline in several cardiometabolic measures.

The trial has shown that treatment can “achieve control of the disease but not a cure,” Carel le Roux, MD, PhD, of University College Dublin in Ireland, told attendees. While metabolic and functional complications of obesity improved and remained improved, “uncertainty remains regarding what happens with appetite behavior,” he said.

MarieElena Cordisco, NP-C, APRN, senior director of therapeutic strategy lead metabolic at Worldwide Clinical Trials in Triangle Park, North Carolina, said she came into the SURMOUNT-1 presentation without specific expectations and found the results “very exciting.”

“I’m always interested in what’s preventing progression of diabetes or reversing diabetes, so that’s what really struck me from the data,” Cordisco told MedPage Today. “I don’t think there’s anything quite like it. We haven’t seen this before, and I’m excited for the next round of the medications.”

Cordisco also noted the importance of teaching people with obesity how to eat and maintain a healthy lifestyle, as diabetes education does, while they take the medications. “You can’t just have drugs, you have to have the rest of it too, the lifestyle intervention, counseling, exercise, teaching people how to cook and eat,” she said.

Louis Aronne, MD, a professor of metabolic research at Weill Cornell Medicine in New York City, presented the study design, which included 1,032 participants with prediabetes tracked for 176 weeks in nine countries across four continents, with 45% of participants from the U.S. The participants’ average HbA1c was 5.8, and they weighed an average of about 236 pounds at baseline with an average 38.8 BMI and 116.5 cm waist circumference; 35.8% had dyslipidemia and 41.2% had hypertension.

At baseline, the participants were an average age of 48, and were 63.9% female, 73.4% white, and 46.7% Hispanic/Latino. The 461 U.S. patients were an average of around 50 years old and 65.3% female. The race and ethnicity breakdown of the U.S. participants was generally representative of U.S. demographics, including 82.2% white, 13% Black, 2.2% Asian, and 23.2% Hispanic/Latino.

There were 253 participants in the 15-mg group, 262 in the 10-mg group, 247 in the 5 mg-group, and 270 were assigned to placebo. All participants receiving tirzepatide started at 2.5 mg for the first 4 weeks and then titrated up in 2.5 mg increments every 4 weeks until they reached the maximum dose for their group; they also had a reduced calorie diet and increased physical activity as well.

Nearly all participants taking any dose of tirzepatide (91-95%) lost at least 5% of their body weight, compared to only 25% of those in the placebo group, Jastreboff reported. More than half (63%) taking 15 mg of tirzepatide lost at least 20% of their body weight, compared to 48% taking 10 mg, 28% taking 5 mg, and 2% on placebo. At least 25% body weight loss occurred in 43% taking the highest dose, 33% taking the middle dose, and 16% taking the lowest dose.

Taking tirzepatide reduced the risk of progressing to diabetes by 93% (HR 0.07, P<0.001) compared to placebo over 3 years, with only 1.3% of participants on tirzepatide developing diabetes compared to 13.3% taking placebo. The contribution of weight reduction accounted for more than half (55.2%) of the reduction in risk of diabetes.

Reversion from prediabetes to normoglycemia occurred in 94.5% of those taking any dose of tirzepatide compared to 60.4% of those taking placebo. None of the participants taking the 15 mg dose developed diabetes, and only 2.8% of them still had prediabetes. Participants taking tirzepatide had an average of 0.5-0.65% absolute decrease in HbA1c.

“The decrease in waist circumference was on average up to eight times greater with tirzepatide than with placebo,” Jastreboff said. Those taking placebo lost an average 1 inch compared with 7.9 inches with 15 mg of tirzepatide, 7.2 inches with 10 mg, and 5.1 inches with 5 mg.

“Improvement in systolic blood pressure occurred during dose escalation, was maintained throughout the treatment period, and did not appear to be dose dependent,” Jastreboff said. Systolic blood pressure fell 0.2 mmHg in the placebo group compared with 5.9-8.5 mmHg in the tirzepatide groups. Diastolic blood pressure similarly fell 1.9 mmHg in placebo participants compared with 4.2-5.9 mmHg in tirzepatide participants.

Consistent improvements occurred across all lipid levels, Jastreboff reported, with pooled tirzepatide participants experiencing an average 14% increase in HDL and 32.4% drop in triglycerides, compared with 2.5% and 4.2%, respectively, with placebo.

When patients went off tirzepatide for 17 weeks, follow-up at week 193 revealed that participants regained an average 7% of weight, and eight additional participants in the tirzepatide groups developed type 2 diabetes. Average HbA1c levels and systolic and diastolic blood pressure began increasing back toward the baseline for participants no longer taking tirzepatide.

Regarding safety outcomes, Sean Wharton, MD, PharmD, an assistant professor of internal medicine at the University of Toronto in Canada, reported that no imbalance in deaths occurred across the treatment groups, and rates of treatment-emergent and serious adverse events were similar across all groups. Serious adverse events were experienced by 13.4% of participants taking 15 mg of tirzepatide, 14.5% of those taking 10 mg, 12.6% of those taking 5 mg, and 11.9% of those on placebo. More tirzepatide participants (7.3-12.3%) than placebo participants (5.9%) discontinued the drug due to side effects, predominantly gastrointestinal ones.

The most common adverse event besides COVID-19 was nausea, occurring in 31.6% of the 15-mg group, 32.8% of the 10-mg group, 24.3% of the 5-mg group, and 11.9% of the placebo group. Diarrhea (19.8-28.6% across doses), constipation (15.8-21.8%), and dyspepsia (7.7-14.2%) were similarly more prevalent with tirzepatide than with placebo (10%, 8.1%, and 5.6%, respectively). Vomiting occurred in 14.2% of high-dose, 10.7% of medium-dose, and 7.7% of low-dose tirzepatide groups, compared with 1.5% with placebo.

As seen with other obesity treatments, including surgery, gall stones were more common with tirzepatide (2-3.6%) than with placebo (1.9%), but cholecystitis rates were similar across all groups.

“Most adverse events of nausea, vomiting, and diarrhea occurred primarily during the dose-escalation period and were mostly mild-to-moderate in severity,” Wharton reported, and no new or unexpected safety signals emerged during the study.

Three cases of acute pancreatitis occurred in the 5-mg group, leading to discontinuation, and two pulmonary emboli occurred in placebo participants that led to discontinuation.