Semaglutide trumps liraglutide for weight loss in nondiabetic overweight or obese patients

Nondiabetic adults with overweight or obesity lost more weight when treated with once-weekly semaglutide than once-daily liraglutide, as demonstrated by results of the phase IIIb STEP* 8 trial.

“Among adults with overweight or obesity without diabetes, once-weekly subcutaneous semaglutide compared with once-daily subcutaneous liraglutide, added to counselling for diet and physical activity, resulted in significantly greater weight loss at 68 weeks, accompanied by significantly greater improvements in several cardiometabolic risk factors,” said the authors.

In this US-based, multicentre trial, 338 nondiabetic adults (mean age 49 years, 78.4 percent female, 73.7 percent White) who were overweight or obese (≥27 and ≥30 kg/m², respectively; mean 37.5 kg/m²) with ≥1 weight-related comorbidities** were randomized 3:1:3:1 to receive subcutaneous semaglutide (2.4 mg once/week; escalated from 0.25 mg over 16 weeks) or matching placebo, or liraglutide (3.0 mg once/day; escalated from 0.6 mg over 4 weeks), or matching placebo, in addition to recommended diet and physical activity, for 68 weeks. The active treatment groups were double blinded to their respective placebos but not to each other.

Mean body weight and waist circumference at baseline were 104.5 kg and 113.3 cm, respectively. About 36 percent had prediabetes.

There was a significantly greater reduction in body weight from baseline to week 68 in patients who received semaglutide compared with those who received liraglutide (mean change -15.8 percent vs -6.4 percent; difference, -9.4 percentage points; p<0.001). [JAMA 2022;327:138-150]

Patients in the semaglutide group had a higher likelihood of achieving ≥10 percent weight loss at week 68 than those in the liraglutide group (70.9 percent vs 25.6 percent; odds ratio [OR], 6.3, 95 percent confidence interval [CI], 3.5–11.2; p<0.001).

Similarly, weight loss of ≥15 percent and ≥20 percent at week 68 was significantly more likely with semaglutide than liraglutide (55.6 percent vs 12.0 percent; OR, 7.9, 95 percent CI, 4.1–15.4 and 38.5 percent vs 6.0 percent; OR, 8.2, 95 percent CI, 3.5–19.1, respectively; p<0.001 for both).

Semaglutide outdid liraglutide in multiple cardiometabolic endpoints assessed at week 68 including body weight (difference, -8.5 kg), waist circumference (-6.6 cm), and diastolic blood pressure (difference, -4.5 mm Hg), total cholesterol (difference, -7.0 percent), very low-density lipoprotein cholesterol (-11.0 percent), triglyceride (difference, -11.0 percent), HbA_1c (difference, -0.2 percentage points), fasting plasma glucose (difference, -3.9 mg/dL), and C-reactive protein (difference, -37.2 percent) levels.

In the pooled placebo group, the mean body weight change from baseline was -1.9 percent, with significantly greater weight loss with semaglutide or liraglutide vs placebo (difference, -13.9 and -4.5 percentage points, respectively). Weight loss of ≥10, ≥15, and ≥20 percent was documented in 15.4, 6.4, and 2.6 percent of placebo recipients, respectively.

Side effect profile

Adverse events (AE) occurred in 95.2, 96.1, and 95.3 percent of participants on semaglutide, liraglutide, and placebo, respectively. The most common AEs with semaglutide and liraglutide were gastrointestinal, which occurred in 84.1 and 82.7 percent, respectively, and were mostly mild to moderate, with severe events reported in four and three patients, respectively.

Serious AEs were reported by 7.9, 11.0, and 7.1 percent of semaglutide, liraglutide, and placebo recipients, respectively. One and four patients in the semaglutide and liraglutide groups, respectively, had gallbladder-related issues, while three in each group had malignant neoplasms.

Sixty-seven patients (19.8 percent) permanently discontinued treatment. Discontinuation for any reason was double in the liraglutide vs semaglutide group (27.6 percent vs 13.5 percent), while permanent discontinuation due to AEs occurred in 3.2 and 12.6 percent of semaglutide and liraglutide recipients, respectively. There were no deaths.

However, the authors noted that differing responses to AEs between groups could have affected discontinuation rates. “[S]emaglutide was administered at a lower dose, whereas liraglutide was discontinued and had to be re-escalated if restarted,” they said. As such, more liraglutide than semaglutide recipients may have permanently discontinued treatment following an AE.  

Variety of drugs needed to battle obesity epidemic

According to the authors, previous research has suggested that while the weight loss effects of both semaglutide and liraglutide are due to reduced energy intake, the mechanisms behind this reduction may differ between the two drugs.

Despite the findings favouring semaglutide, the authors pointed to the importance of having a variety of obesity drug options that exact effects through different mechanisms and have different AEs and dosing regimens. “[T]he variability in treatment response means an individual’s tolerance and sensitivity to a specific treatment is important for obesity management,” they said.