Semaglutide

Authors:

Philip Whitfield, Sharath Kommu

Findings:

In adults with overweight or obesity (without diabetes), once-weekly 2.4 mg subcutaneous semaglutide plus lifestyle intervention resulted in a mean body weight change of -14.9% from baseline to week 68, compared to -2.4% with placebo. Participants receiving semaglutide also showed greater improvement in cardiometabolic risk factors and participant-reported physical functioning. Nausea and diarrhea were the most common, typically transient and mild-to-moderate, adverse events with semaglutide, leading to more treatment discontinuations compared to placebo.

Participants:

1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes.

Dosage:

Once-weekly subcutaneous semaglutide at a dose of 2.4 mg for 68 weeks.

Study Quality Assessment:

Randomized controlled trial, double-blind, placebo-controlled, multicenter study. N=1961. Duration: 68 weeks of treatment. The primary estimand assessed effects regardless of treatment discontinuation or rescue interventions. Funded by Novo Nordisk. ClinicalTrials.gov number: NCT03548935.

All Effects:

Authors:

Rithwik Goud Burri, Sri Ram Charan Gundapaneni

Study Quality Assessment:

systematic review

Authors:

Ariana M Chao

Findings:

Semaglutide 2.4 mg injected subcutaneously once weekly, as an adjunct to a reduced-calorie diet and physical activity, helps adult patients achieve average weight losses of 9.6–17.4% of initial body weight at week 68, along with improvements in cardiometabolic and psychosocial indices. This paper discusses considerations for the selection of individuals who are candidates for semaglutide and special considerations related to its use, including its efficacy, safety, contraindications (e.g., personal or family history of MTC or MEN 2, hypersensitivity, pregnancy), potential adverse effects (e.g., gastrointestinal, pancreatic events, gallbladder disease), management of comorbidities, drug interactions, insurance coverage, cost, and patient preferences.

Participants:

The paper discusses semaglutide for chronic weight management in adults with overweight or obesity. This includes individuals with or without type 2 diabetes, as detailed in the reviewed STEP clinical trial program (e.g., STEP 1: 1961 adults without type 1 or 2 diabetes; STEP 2: 1210 adults with type 2 diabetes and overweight/obesity; STEP 3: 611 participants without diabetes; STEP 4: 803 adults without diabetes; STEP 5: 304 adults without diabetes; STEP 6: 401 adults from East Asia, with or without type 2 diabetes; STEP 8: 338 adults with overweight or obesity without diabetes).

Dosage:

Semaglutide 2.4 mg injected subcutaneously once weekly for chronic weight management in adults. The dose is titrated up starting at 0.25 mg once a week with dose increases every 4 weeks until the full dose of 2.4 mg is reached, to minimize gastrointestinal side effects. Other doses mentioned in specific trials or contexts include 1.0 mg and 1.7 mg once weekly.

Study Quality Assessment:

The paper reviews evidence primarily from the Semaglutide Treatment Effect in People with Obesity (STEP) program, described as a series of multicenter, phase 3 randomized clinical trials. Specific trials (e.g., STEP 1, 2, 3, 4, 5, 6, 8) are detailed with methodologies including randomization (e.g., STEP 1, 2, 3, 4, 5, 6, 8), double-blind design (e.g., STEP 1, 2, 3, 5, 6), placebo-control (e.g., STEP 1, 2, 3, 4, 5, 6, 8), and specific sample sizes (e.g., STEP 1 N=1961, STEP 2 N=1210, STEP 3 N=611, STEP 4 N=803, STEP 5 N=304, STEP 6 N=401, STEP 8 N=338). The paper acknowledges limitations such as the relatively short duration of most studies for assessing rare, long-term adverse events (e.g., thyroid C-cell tumors, pancreatic cancer) and that some studies (CVOTs and phase 3) may not have been sufficiently powered for their detection. Disclosures of funding for some authors' efforts and potential conflicts of interest are provided.

All Effects:

Authors:

Abdelrahman Abaza, Advait M Vasavada, Akhil Sadhu, Carla Valencia, Hameeda Fatima, Ijeoma Nwankwo, Mahvish Anam, Shrinkhala Maharjan, Zainab Amjad

Findings:

The systematic review of 12 RCTs found that semaglutide (oral and subcutaneous) is safe and effective in treating obesity, leading to significant weight loss in adults with overweight or obesity, including those with type 2 diabetes. Some studies indicated a dose-dependent effect. The most commonly reported adverse events were gastrointestinal. Further trials with larger, diverse samples and longer follow-up are needed to fully determine its efficacy, safety, required dosage, and treatment duration.

Participants:

This systematic review analyzed 12 Randomized Controlled Trials (RCTs). Participants in these trials were adults with obesity or overweight, some with type 2 diabetes (T2D). Specific trials detailed participant numbers (e.g., N=30 to N=3297), mean ages (e.g., 42 to 66 years), and gender distributions. For example, the FDA approval for semaglutide 2.4 mg is for adults with overweight (BMI >27 kg/m2) with at least one weight-associated condition, or adults with BMI of 30 kg/m2 or greater.

Dosage:

Semaglutide 2.4 mg subcutaneously once a week is FDA approved for adults with overweight (BMI >27 kg/m2 with at least one weight-associated condition) or adults with BMI of 30 kg/m2 or greater. The reviewed RCTs investigated various dosages: subcutaneous semaglutide (e.g., 0.25 mg, 0.5 mg, 1 mg, 2.4 mg once weekly) and oral semaglutide (e.g., 3 mg, 7 mg, 14 mg daily). Some studies noted dose-dependent effects on weight loss.

Study Quality Assessment:

Systematic review of 12 Randomized Controlled Trials (RCTs). The review followed PRISMA 2020 Guidelines. Databases searched include PubMed, ScienceDirect, and Google Scholar. Inclusion criteria specified English language, adult human-based studies, free full text, published between 2012 and May 2022. Data extraction was done by two independent researchers using Rayyan Software. Risk and quality assessment used the Revised Cochrane’s Risk of Bias Tool for RCTs; trials satisfying >70% for quality and grade were selected. Many individual trials were described as randomized, double-blind, and placebo-controlled. Limitations acknowledged: relatively small number of studies (12) included, restriction to English language and free full-text articles, and some original studies had relatively small sample sizes of overweight or obese individuals.

All Effects:

Authors:

Wissam Ghusn

Findings:

In this cohort study of 175 patients with overweight or obesity, semaglutide treatment was associated with a mean total body weight loss of 5.9% (6.7 kg) at 3 months and 10.9% (12.3 kg) at 6 months. These real-world outcomes were similar to those observed in randomized clinical trials, suggesting semaglutide's applicability for treating patients with overweight or obesity in regular clinical settings. Patients with type 2 diabetes experienced significantly less weight loss compared to those without type 2 diabetes.

Participants:

N=175 adults (132 women [75.4%]; mean age 49.3 years; mean BMI 41.3) with overweight or obesity (BMI ≥27) treated with semaglutide for weight loss at a referral center for weight management. Exclusions included a history of bariatric procedures, taking other antiobesity medications, active malignant neoplasm, or pregnancy. Data for 102 patients were available at the 6-month follow-up.

Dosage:

Patients were prescribed weekly semaglutide subcutaneous injections with doses including 0.25 mg, 0.5 mg, 1.0 mg, 1.7 mg, and 2.4 mg, for the primary goal of weight loss. The study aimed to assess outcomes with doses used in randomized clinical trials for obesity (i.e., 1.7 mg and 2.4 mg weekly). In the analyzed cohort, 77 patients (44.0%) received these higher doses (1.7 mg or 2.4 mg), while 98 patients (56.0%) received lower doses (0.25 mg, 0.5 mg, or 1.0 mg).

Study Quality Assessment:

Retrospective cohort study (N=175 at 3 months, N=102 at 6 months) using electronic medical records from the Mayo Clinic Health System. The study followed the STROBE reporting guideline. It received Mayo Clinic institutional review board approval, and the need for informed consent was waived. Funding was provided by the National Institutes of Health (grant K23-DK114460 to Dr. Acosta); the funding source had no role in the study design, conduct, data management, analysis, interpretation, or manuscript preparation/submission. Limitations acknowledged include: observational nature (no control group), potential overestimation of association due to exclusion of patients without 3-month follow-up, limited generalizability (mostly White female patients), possibility of recall bias for medication start/end dates, use of some self-reported weights, and potential for coding errors or missing data from EMRs.

All Effects: