More STEP Data: Semaglutide Cuts Weight, Cravings, Beats Liraglutide

Marlene Busko

November 11, 2021

The STEP 5 clinical trial extends favorable weight loss from 1 year out to 2 years for the glucagon-like peptide-1 (GLP-1) agonist semaglutide (Wegovy, Novo Nordisk), given as a once-weekly 2.4-mg subcutaneous injection, and some food cravings were improved in a subgroup analysis.

In another study, STEP 8, weight loss was greater at 68 weeks with semaglutide subcutaneous injection than with a 3-mg daily subcutaneous injection of another GLP-1 agonist, liraglutide (Saxenda, Novo Nordisk), approved earlier for weight loss.

Researchers presented these promising outcomes, with no new safety signals, at ObesityWeek® 2021.

However, there is more to learn about the drug class, researchers agree. Follow-up is still relatively short for a chronic disease and many patients have gastrointestinal side effects with semaglutide, one expert cautions.

The key findings were:

  • In STEP 5, combined with lifestyle intervention (a reduced-calorie meal plan and advice about physical activity), weekly injection of 2.4 mg semaglutide led to:

    • 15.2% weight loss, compared with 2.6% weight loss with placebo at 2 years (P < .0001);

    • 77% of patients losing at least 5% of their weight, compared with 34% of patients in the placebo group at 2 years (P < .0001);

    • significantly greater improvement in overall control of cravings, and craving for savory foods, in a subset of patients, versus placebo, but questionnaire scores for positive mood and craving for sweet foods were similar in both groups.

  • In STEP 8, mean body weight at 68 weeks was 15.8% lower with 2.4 mg/week subcutaneous semaglutide plus lifestyle changes versus 6.4% lower with 3.0 mg/day subcutaneous liraglutide plus lifestyle changes (P < .001).

Can Treat to a Target Weight-Loss Range

Dr W. Timothy Garvey

The undiminished weight loss efficacy in the 2-year data for STEP 5 "portends well," said W. Timothy Garvey, MD, following his presentation of the results.

"I think this is a new era in obesity care," said Garvey, director of the diabetes research center at the University of Alabama at Birmingham. Semaglutide "essentially doubles weight loss efficacy" compared to the other approved pharmacotherapies for obesity.

With this degree of potential weight loss, clinicians "can use weight as a biomarker and treat to a target [weight-loss] range," he said.

Expounding on this in an interview with Medscape Medical News, Garvey noted that, as stated in the 2016 American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) clinical practice guidelines for medical care of patients with obesity, of which he was lead author, "the objective of care in obesity is to increase health of patients and prevent or treat complications."

Semaglutide "can treat to a range of weight loss of 10% to 20% in the majority of patients," which is associated with improvements in cardiovascular and metabolic risk factors.

In STEP 5, of the 51% of patients in the semaglutide group who had prediabetes at enrollment, 80% had normal glycemia at 2 years; however, the trial was not powered nor designed to investigate this.

More data are needed to inform long-term care decisions. The ongoing SELECT cardiovascular outcomes trial of semaglutide, with expected primary study completion on September 28, 2023, should provide more information.

Weight Loss Plus Reduced Cravings

Dr Sean Wharton

In another presentation, Sean Wharton, MD, PharmD, said, "In adults with overweight or obesity, substantial weight loss with semaglutide 2.4 mg was accompanied by short- and long-term improvements in control of eating."

"Most patients living with obesity who are attempting to decrease calories will have food cravings, based on the biological parameters of weight preservation," Wharton, medical director at the Wharton Medical Clinic, in Hamilton, Ontario, Canada, explained in an email to Medscape Medical News.

The degree of craving varies from patient to patient, likely based on genetics, he added. Research in this field is still emerging.

"I believe that semaglutide 2.4 mg is a game-changer in the field of weight management, and it will change the dialogue for insurance plans and with policymakers regarding coverage for this medication," said Wharton.

"The data from the STEP programs are very strong. I am certainly hoping for a change to bias against covering these medications that we have seen in the past," he said.

Clinically Meaningful Weight Loss

When presenting the STEP 8 findings, Domenica M. Rubino, MD, said: "Participants were significantly more likely to achieve clinically meaningful weight loss thresholds with semaglutide 2.4 mg vs liraglutide 3.0 mg, accompanied by greater improvements in cardiometabolic risk factors."

For example, patients can have better mobility, which is important for quality of life, Rubino, director of the Washington Center for Weight Management and Research, in Arlington, Virginia, noted. 

A smaller percentage of patients respond to liraglutide, she added. Clinicians need to individualize treatment.

When asked, "How do you choose which medical therapy?" Rubino responded: "We sit and talk." Finding the medical therapy that fits the patient depends on things such as the patient's insurance coverage and ability to tolerate side effects such as dehydration, diarrhea, and nausea.   

When asked, "How do you switch from liraglutide to semaglutide?" she noted that there are no current guidelines for this. "You have to be careful. Start on the lowest dose of Wegovy. Be cautious, conservative."  

Still Early Days, Caveats Remain

Dr Julie R. Ingelfinger

"The STEP trials as a group appear to be making the case that obesity may now be considered a medically manageable disease, based on the experience with semaglutide," Julie R. Ingelfinger, MD, who was not involved with the research, commented in an email to Medscape Medical News.

"STEP 5 and 8 may suggest that weight loss occurs and is sustainable in overweight persons without diabetes with one or more comorbidities or in obese persons without diabetes," added Ingelfinger, professor of pediatrics, Harvard Medical School, consultant in pediatric nephrology, Massachusetts General Hospital, Boston, Massachusetts, and deputy editor, The New England Journal of Medicine.

However, "even 2 years, in the case of STEP 5, and ~68 weeks in the case of STEP 8, may not be long enough to know whether semaglutide is as promising as these brief summaries (abstracts) suggest," she cautioned.

"Obesity is a chronic condition, and very long-term therapy and management are required," Ingelfinger continued.

"Further, it is hard to generalize when gastrointestinal adverse events are common in a study," she said. For example in STEP 8, they were just as common with semaglutide as with the comparator liraglutide, she noted.

"The racial and ethnic representativeness of these studies does not reflect population distributions in the US, limiting generalization," she continued.

"So, there remain caveats in interpreting these data."

STEP 5 Weight Loss Efficacy and Safety at 2 Years

Garvey reported that STEP 5 was a phase 3b trial that randomized 304 adults in the United States, Canada, Hungary, Italy, and Spain who were 18 years and older, with a body mass index (BMI) ≥ 27 kg/m2 with at least one weight-related comorbidity (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease) or a BMI ≥ 30 kg/m2, without type 2 diabetes, to receive semaglutide or placebo plus lifestyle intervention.

Most participants were women (78%) and White (93%). On average, they were 47 years old, weighed 106 kg (223.7 pounds), had a BMI of 38.5 kg/m2, a waist circumference of 115.7 cm (45.6 inches), and an A1c of 5.7%.

A total of 87% of patients in the semaglutide group and 73% of patients in the placebo group completed the trial.

At 104 weeks, participants were more likely to lose ≥ 10%, ≥ 15%, and ≥ 20% of body weight with semaglutide vs placebo (61.8% vs 13.3%, 52.1% vs 7.0%, and 36.1% vs 2.3%, respectively; P < .0001 for all).

Patients in the semaglutide group had greater health improvements in cardiovascular risk factors (waist circumference, systolic and diastolic blood pressure, and C-reactive protein) and metabolic risk factors (A1c, fasting plasma glucose, fasting serum insulin, and triglycerides) than those in the placebo group (P < .05 for all).

Safety and tolerability were consistent with adverse events seen with this drug class, with no new safety signals.

Control of Eating Questionnaire Findings at 2 Years in STEP 5

Wharton and colleagues assessed changes in responses to the Control of Eating questionnaire at baseline and at 20, 52, and 104 weeks in patients from the US and Canada in the STEP 5 trial (88 patients in the semaglutide group and 86 patients in the placebo group).

The questionnaire consisted of 19 questions grouped into four categories: control of food cravings, craving for savory foods (salty and spicy, dairy, or starchy foods), craving for sweet foods (chocolate, sweet foods, or fruit/fruit juice), and positive mood.

At week 104, patients in the semaglutide group had significantly greater improvements in scores for craving for salty and spicy, dairy, and starchy foods, and resisting cravings.   

Semaglutide vs Liraglutide, 68-Week Efficacy and Safety in STEP 8

STEP 8 randomized 338 US adults without diabetes and a BMI ≥ 27 kg/m2 plus one or more weight-related comorbidities or a BMI ≥ 30 kg/m2 3:1 to semaglutide 2.4 mg once weekly (n = 126) or matching placebo, or 3:1 liraglutide 3.0 mg once daily (n = 127) or matching placebo, plus lifestyle intervention.

Most participants were women (78%) and were a mean age of 49, had a mean body weight of 104.5 kg, and had a mean BMI of 37.5 kg/m2.

In STEP 8, more participants achieved ≥ 10%, ≥ 15%, and ≥ 20% weight loss with semaglutide than with liraglutide (70.9% vs 25.6%, 55.6% vs 12.0%, and 38.5% vs 6.0%, respectively; P < .001 for all odds ratios).

Semaglutide improved waist circumference, A1c, and C-reactive protein vs liraglutide (unadjusted P < .001 for all).

Gastrointestinal adverse events were reported by 84% and 83% of participants receiving semaglutide and liraglutide, respectively. Most events were mild/moderate and transient, with prevalence declining over time.

Fewer participants stopped treatment due to adverse events with semaglutide than liraglutide (3.2% vs 12.6%).

Garvey has reported serving as a site principal investigator for multicentered clinical trials sponsored by his university and funded by Eli Lilly, Novo Nordisk, and Pfizer. He has also reported serving as a volunteer consultant on advisory committees for Jazz Pharmaceuticals, Boehringer Ingelheim, Novo Nordisk, and Pfizer and received no financial compensation. Wharton has reported being on speakers bureaus and advisory boards and receiving academic honoraria from Novo Nordisk, Bausch Health Canada, Eli Lily, and Boehringer Ingelheim Canada, and receiving research grants from Novo Nordisk and Bausch Health Canada. Rubino has reported being a clinical investigator for Boehringer Ingelheim and AstraZeneca and receiving speaker fees, consulting fees, and honoraria from Novo Nordisk, and being a shareholder in Novo Nordisk. Ingelfinger has reported no relevant financial relationships.

ObesityWeek® 2021. Oral abstracts 96, 95, 78. Presented November 5, 2021.

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