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Good and bad news. It is clear that the pharmaceuticalization of obesity means its treatment will need to be long-term.
Should the emergence of so-called glucagon-like peptide-1 receptor agonists as a treatment for obesity be celebrated? Yes, if you have vested interests in the pharmaceutical industry and you think the long-term risks of these treatments are less than the comorbidities associated with obesity. No, if you think obesity can be managed successfully with lifestyle and behavioural modifications.
The study below of once-weekly subcutaneous semaglutide shows that if you stop the drug after 20 weeks the treatment effect of continued weight loss is reversed and the inevitable weight gain
The class of glucagon-like peptide-1 receptor agonists increase the production of insulin. Insulin lowers the blood sugar level, enhances the growth of β cells in the pancreas, which is the site of insulin production. The downside of increased insulin production is an increased risk of some cancers. In the STEP 4 trial there appears to be a secondary malignancy signal:
“During the randomized period, malignant neoplasms occurred in 1.1% of participants taking continued semaglutide vs 0.4% taking placebo. Of the events in the continued semaglutide group, 3 were breast neoplasms (intraductal proliferative breast lesion, invasive breast cancer, and invasive ductal breast carcinoma), and the remaining 3 had no apparent clustering (endometrial adenocarcinoma, marginal zone lymphoma, and malignant melanoma). One event occurring in the placebo group was metastatic lung cancer.“
Maybe we should go back to basics and recognise obesity as a metabolic disease that could be managed with lifestyle modifications and behavioural change before resorting to pharmaceuticals? Or should the prescription pad take precedence?
Rubino et al. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity. The STEP 4 Randomized Clinical Trial. JAMA. Published online March 23, 2021. doi:10.1001/jama.2021.3224
Question: What effect does continued treatment with 2.4 mg of subcutaneous semaglutide have on the maintenance of body weight loss in adults with overweight or obesity without diabetes?
Findings: In this randomized clinical trial of adults with overweight or obesity, 803 participants completed a 20-week run-in of weekly treatment with subcutaneous semaglutide, 2.4 mg, with a mean weight loss of 10.6%, and were randomized to continued treatment with subcutaneous semaglutide vs placebo for an additional 48 weeks. At the end of this time, mean weight change was −7.9% vs +6.9%, respectively, a difference that was statistically significant.
Meaning: Among adults with overweight or obesity completing a 20-week run-in period, maintaining treatment with subcutaneous semaglutide compared with switching to placebo resulted in continued weight loss.
Importance: The effect of continuing vs withdrawing treatment with semaglutide, a glucagon-like peptide 1 receptor agonist, on weight loss maintenance in people with overweight or obesity is unknown.
Objective: To compare continued once-weekly treatment with subcutaneous semaglutide, 2.4 mg, with switch to placebo for weight maintenance (both with lifestyle intervention) in adults with overweight or obesity after a 20-week run-in with subcutaneous semaglutide titrated to 2.4 mg weekly.
Design, Setting, and Participants: Randomized, double-blind, 68-week phase 3a withdrawal study conducted at 73 sites in 10 countries from June 2018 to March 2020 in adults with body mass index of at least 30 (or ≥27 with ≥1 weight-related comorbidity) and without diabetes.
Interventions: A total of 902 participants received once-weekly subcutaneous semaglutide during run-in. After 20 weeks (16 weeks of dose escalation; 4 weeks of maintenance dose), 803 participants (89.0%) who reached the 2.4-mg/wk semaglutide maintenance dose were randomized (2:1) to 48 weeks of continued subcutaneous semaglutide (n = 535) or switched to placebo (n = 268), plus lifestyle intervention in both groups.
Main Outcomes and Measures: The primary endpoint was percent change in body weight from week 20 to week 68; confirmatory secondary endpoints were changes in waist circumference, systolic blood pressure, and physical functioning (assessed using the Short Form 36 Version 2 Health Survey, Acute Version [SF-36]).
Results: Among 803 study participants who completed the 20-week run-in period (with a mean weight loss of 10.6%) and were randomized (mean age, 46 [SD, 12] years; 634 [79%] women; mean body weight, 107.2 kg [SD, 22.7 kg]), 787 participants (98.0%) completed the trial and 741 (92.3%) completed treatment. With continued semaglutide, mean body weight change from week 20 to week 68 was −7.9% vs +6.9% with the switch to placebo (difference, −14.8 [95% CI, −16.0 to −13.5] percentage points; P < .001). Waist circumference (−9.7 cm [95% CI, −10.9 to −8.5 cm]), systolic blood pressure (−3.9 mm Hg [95% CI, −5.8 to −2.0 mm Hg]), and SF-36 physical functioning score (2.5 [95% CI, 1.6-3.3]) also improved with continued subcutaneous semaglutide vs placebo (all P < .001). Gastrointestinal events were reported in 49.1% of participants who continued subcutaneous semaglutide vs 26.1% with placebo; similar proportions discontinued treatment because of adverse events with continued semaglutide (2.4%) and placebo (2.2%).
Conclusions and Relevance: Among adults with overweight or obesity who completed a 20-week run-in period with subcutaneous semaglutide, 2.4 mg once weekly, maintaining treatment with semaglutide compared with switching to placebo resulted in continued weight loss over the following 48 weeks.
Trial Registration ClinicalTrials.gov Identifier: NCT03548987
Twitter: @gavinGiovannoni Medium: @gavin_24211
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