Diabetes Medication Semaglutide Demonstrates Safety in Adults Aged 55 and Older, Supports Study in Alzheimer Disease

Marwan Sabbagh, MD

Pooling data from 3 major phase 3 trials, results suggest that semaglutide (Novo Nordisk), an FDA-approved agent for type 2 diabetes (T2D) and obesity, is safe to administer among adults aged 55 years and older. Overall, these data support the evaluation of the glucan-like peptide-1 (GLP-1) analogue in an older population with early Alzheimer disease (AD) in evoke.

Presented at the 2023 Alzheimer’s Association International Conference (AAIC), held June 16-20, in Amsterdam, Netherlands, the analysis included data from the PIONEER (NCT02906930), SUSTAIN (NCT02207374; NCT02254291), and STEP (NCT03548935) clinical programs. Patients were on a wide range of semaglutide doses throughout those programs, including 3, 7, and 14 mg for PIONEER, 0.5 or 1 mg for SUSTAIN, and 2.4 mg in STEP.

Led by Marwan Sabbagh, MD, a behavioral neurologist at Barrow Neurological Institute, the analysis comprised of 8595 participants aged 50 and older. Semaglutide was administered once-daily in an oral fashion in PIONEER, while patients received once-weekly subcutaneous doses in SUSTAIN and STEP. At baseline in the PIONEER, SUSTAIN, and STEP pooled datasets, mean age was 64.3 (SD, 6.4), 63.5 (SD, 6.1), and 62.0 (SD, 5.6) years, respectively, and mean body mass index was 30.8 (SD, 6.2), 31.0 (SD, 6.2), and 35.6 (SD, 6.2) kg/m2.

At the conclusion of the analysis, the percentage of participants with adverse events (AEs) that led to discontinuation of semaglutide were 10.2%, 9.1%, and 7.7%, in PIONEER-SUSTAIN, and STEP programs, respectively, compared with rates of 5.2%, 3.9%, and 3.3% for comparator arms. Serious AEs were recorded in 10.1%, 7.5%, and 12.4% of patients on semaglutide in the same respective studies vs rates of 14.5%, 7.3%, and 10.1% for those on either comparator or placebo group.

Gastrointestinal disorders were the most frequently reported AE system organ class, with nausea, diarrhea, constipation, and vomiting the most frequent gastrointestinal AEs in the semaglutide arm of each pooled dataset. Semglutide-treated individuals showed greater reductions in weight loss relative to its comparator in all the trials, with a tendency to plateau over time. The most noticeable difference between the arms in body weight change occurred in the STEP program. Overall, general AEs were recorded in 75.6%, 73.7%, and 91.9% of patients on semaglutide in PIONEER, SUSTAIN, and STEP, respectively, vs rates of 73.2%, 68.2%, and 85.9% for the comparator/placebo groups.

READ MORE: Alzheimer Disease Pipeline Update: Inside Look at Promising Agents

Semaglutide belongs to a class of medications known as GLP-1 receptor agonists. It mimics the GLP-1 hormone that is released in the gastrointestinal tract in response to eating. One role of GLP-1 is to prompt the body to produce more insulin, which reduced blood glucose. There are currently 3 FDA-approved semaglutide projects, including Ozempic injection and Rybelsus tablets, which are designed to lower blood sugar levels in adults with T2D, and Wegovy injection, a therapy to help adults and children with obesity lose weight and keep the weight off.

Research has suggested that patients with T2D have increased risk of dementia. A 2022 study assessed exposure to GLP-1 receptor agonists in patients with T2D and a subsequent diagnosis of dementia using 2 large data sources with long-term follow-up. Overall, findings showed that the dementia rate was lower both in patients randomized to GLP-1 receptor agonists vs placebo (HR, 0.47; 95% CI, 0.25-0.86) and in a nationwide Danish registry-based cohort (HR, 0.89; 95% CI, 0.86-0.93) with yearly increased exposure to GLP-1 receptor agonists.²

In December 2020, Novo Nordisk announced it would begin development of semaglutide in patients with early-stage AD. Beginning in the first half of 2021, the phase 3a program was planned to enroll 3700 individuals for a planned 2-year course of a once-daily 14 mg dose of semaglutide or placebo. Two, phase 3 trials, each enrolling 1840 people with mild cognitive impairment or mild dementia because of AD, confirmed by amyloid PET or cerebrospinal fluid amyloid-ß42, were registered by the company months later in March 2021.³

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REFERENCES
1. Sabbagh M, Boschini C, Cohen S, et al. Safety profile of semaglutide in people aged 55 years and over: pooled data from the PIONEER, SUSTAIN, and STEP phase 3 clinical programs. Presented at: AAIC 2023; June 16-20; Amsterdam, Netherlands. Abstract 76540
2. Medications containing semaglutide marketed for type 2 diabetes or weight loss. FDA. Updated May 31, 2023. Accessed July 18, 2023. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/medications-containing-semaglutide-marketed-type-2-diabetes-or-weight-loss

3. Norgaard CH, Friedrich S, Hansen CT, et al. Treatment with glucagon-like peptide-1 receptor agonists and incidence of dementia: data from pooled double-blind randomized controlled trials and nationwide disease and prescription registers. Alzheimers Dement. 2022;8(1):e12268