Abstract
INTRODUCTION
The evoke/evoke+ trials are investigating semaglutide in a population with early Alzheimer's disease (AD). Specific analyses of semaglutide safety data in older adults are limited; therefore, in the current analysis, we aimed to evaluate safety considerations with semaglutide in adults ≥ 65 years.
METHODS
Adverse event (AE) data from three semaglutide phase 3a programs in participants ≥ 65 years with type 2 diabetes and/or overweight/obesity were pooled. Change in body weight was also assessed in a smaller subset of participants ≥ 65 years.
RESULTS
The analysis included 3529 participants ≥ 65 years. Baseline mean age and body mass index in participants ≥ 65 years were 69.3 to 70.2 years and 29.7 to 35.4 kg/m2, respectively, compared to 47.8 to 58.5 years and 31.3 to 36.7 kg/m2 in the overall population. AEs with semaglutide occurred in 73.6% to 92.4% of participants ≥ 65 years versus 73.2% to 90.8% of the overall population. AEs with semaglutide leading to permanent discontinuation appeared to be more frequent in participants ≥ 65 years (9.3%–12.4%) versus the overall population (5.7%–8.7%). Gastrointestinal disorders were the most frequently reported AEs with semaglutide in participants ≥ 65 years (44.6%–73.8%) and in the overall population (39.1%–73.4%). Participants aged ≥ 65 years receiving semaglutide had an estimated weight loss of 3.8% at week 52 compared to 0.1% with placebo.
DISCUSSION
Age ≥ 65 years did not appear to affect the safety considerations of semaglutide. The ongoing evoke/evoke+ trials will elucidate the balance of efficacy and safety in the treatment of early AD with semaglutide.
Highlights
This was a post hoc analysis evaluating adverse event (AE) data of semaglutide in people ≥ 65 years.
The most common AE with semaglutide was gastrointestinal (GI).
GI event rates were similar in people ≥ 65 years and the overall study populations.
Keywords: adverse event, Alzheimer's disease, early, glucagon‐like peptide‐1 analogue, pooled analysis, semaglutide, safety
1. BACKGROUND
Alzheimer's disease (AD) is the leading cause of dementia. 1 Older age, cardiovascular disease, type 2 diabetes (T2D), and obesity are among the risk factors for AD. 2 , 3
Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) have been used for the treatment of T2D and obesity since 2005 and 2010, respectively. 4 , 5 Results from clinical trials and real‐world evidence in people with T2D indicate that GLP‐1RAs are associated with a reduction in dementia risk in this population, 6 , 7 , 8 , 9 , 10 as well as reduced risk for first‐time AD diagnosis. 11 Analyses of data from a nationwide, Danish, registry‐based cohort of people with T2D reported that the use of GLP‐1RAs was associated with lower odds of dementia 6 and that increased exposure to GLP‐1RAs reduced the rate of dementia compared with other second‐line diabetes treatments. 7 In an analysis of people with T2D who received glucose‐lowering monotherapy, those receiving GLP‐1RAs were found to have a lower risk of AD than those receiving metformin. 8 Another analysis using pooled data from people with T2D in three randomized cardiovascular outcome trials found a lower rate of dementia in people treated with GLP‐1RAs compared with those receiving placebo. 7 Finally, a post hoc analysis of a randomized, placebo‐controlled trial in people with T2D and elevated cardiovascular risk showed that treatment with the GLP‐1RA dulaglutide was associated with reduced risk of cognitive impairment after a median follow‐up of 5.4 years. 12
Accumulating preclinical and clinical evidence indicates that GLP‐1RAs impact multiple neuroinflammatory, vascular, and other pathophysiological processes involved in AD. 13 , 14 For example, in mouse models of AD, the GLP‐1RAs liraglutide and semaglutide reduced neuroinflammation, synaptic loss, and cognitive decline (including in memory function), and attenuated expression of various inflammatory genes. 15 , 16 , 17 In a randomized pilot study in people with AD, liraglutide treatment was associated with less decline in cerebral glucose metabolism in cortical regions compared with placebo. 18 Moreover, in a randomized phase 2b trial, individuals with mild‐to‐moderate AD dementia treated with liraglutide showed better cognitive function and greater temporal lobe and whole‐cortex volume on magnetic resonance imaging after 12 months than individuals who received placebo. 19 Clinical studies on T2D and obesity also indicate beneficial effects on peripheral inflammation. 20 , 21 , 22
Given the encouraging results seen with semaglutide and other GLP‐1RAs in preclinical and human studies, two phase 3, randomized, placebo‐controlled trials (evoke and evoke+) are investigating the safety and efficacy of oral semaglutide 14 mg in people with early AD (defined as biomarker‐confirmed, mild cognitive impairment due to AD or mild AD dementia) aged 55 to 85 years. 23 , 24
Semaglutide is approved as pharmacotherapy for T2D (as a once‐weekly subcutaneous [sc] injection at a 0.5, 1.0, or 2.0 mg dose and as once‐daily oral administration at a 7 or 14 mg dose) and obesity (once‐weekly sc injection at a 2.4 mg dose) with no upper age limit. 25 , 26 , 27 , 28 , 29 , 30 The safety profile of semaglutide is well established through large clinical trials in individuals with T2D and with obesity 31 , 32 ; however, specific evaluations of safety data in populations aged ≥ 65 years are limited. 25 , 26 , 27 , 28 , 29 , 30 Thus, in the current analysis, our objective was to evaluate safety data with semaglutide in a population aged ≥ 65 years with a mean age similar to the evoke and evoke+ trials. 23 , 24 Here, we present semaglutide adverse event (AE) data in individuals aged ≥ 65 years from 22 clinical trials of the PIONEER, SUSTAIN, and STEP clinical programs. We also present weight loss data in participants ≥ 65 years with T2D from a subset of four placebo‐controlled PIONEER studies.
2. METHODS
2.1. Data sources
PIONEER, SUSTAIN, and STEP were randomized, double‐blind, comparator‐controlled trials evaluating oral and sc formulations of semaglutide at various doses across different indications. Detailed methods for all trials have been published previously and are referenced in the supporting information (see Table S1). Briefly, the PIONEER clinical program evaluated the effect of once‐daily oral semaglutide 3, 7, or 14 mg versus an active comparator or placebo for 26 to 78 weeks in participants with T2D. The SUSTAIN clinical program evaluated the effect of once‐weekly sc semaglutide 0.5 or 1.0 mg versus active comparator or placebo for 30 to 56 weeks in participants with T2D. Finally, the STEP clinical program evaluated the effect of once‐weekly sc semaglutide 2.4 mg versus placebo for 68 to 104 weeks in people with overweight or obesity with or without T2D. Based on exposure levels measured in other studies of sc and oral semaglutide, semaglutide exposure levels in the STEP program were higher than those studied in SUSTAIN and PIONEER (2.4 mg sc vs. 1 mg sc and 14 mg oral, respectively). 33
In the current analysis, data from participants aged ≥ 65 years were pooled from nine trials in the PIONEER program (PIONEER 1–5 and PIONEER 7–10; PIONEER pool, n = 1901), from seven trials in the SUSTAIN program (SUSTAIN 1–5 and SUSTAIN Japan [NCT02207374 and NCT02254291]; SUSTAIN pool, n = 1147), and from six trials in the STEP program (STEP 1–6; STEP pool, n = 481; Table S1). Informed consent and ethics committee approval were previously obtained for each study included in the present analysis.
2.2. Data analyses
Baseline characteristics and safety data were reported for people ≥ 65 years in the PIONEER, SUSTAIN, and STEP pooled datasets. The age limit used in this analysis was chosen so that the mean age of the population was similar to the mean age of the evoke/evoke+ population.
Safety assessments (data from the on‐treatment period) included the number and type of AEs, with a focus on the most frequently reported AEs (gastrointestinal [GI]). AEs stratified by age subgroup (65–74 and ≥ 75 years) were also assessed.
To provide insights on the effects of semaglutide on body weight, a separate analysis of change in body weight over time in people ≥ 65 years was performed with a pooled dataset comprising PIONEER 1, 4, 5, and 8 only. The PIONEER dataset was selected because these trials most closely resemble evoke and evoke+ with regard to semaglutide dose (14 mg), route of administration (oral), and placebo comparator. Analysis of change in body weight stratified by age subgroup was not performed due to the small sample size, thus limiting reliability.
2.3. Statistical analysis
For baseline characteristics and safety analyses, data were pooled for all oral semaglutide doses (3, 7, and 14 mg) and for the comparators in the PIONEER pool, for all sc semaglutide doses (0.5 or 1.0 mg) and for comparators in the SUSTAIN pool, and for sc semaglutide 2.4 mg and placebo in the STEP pool. Data were analyzed descriptively.
AEs were classified according to system organ classes and preferred terms as defined by Medical Dictionary for Regulatory Activities version 23.1. The AEs reported in this analysis were the most frequently reported AEs (proportion of participants in the safety analysis set with one event or more) according to system organ class in the semaglutide arm of each pooled dataset. To minimize the potential risk of confounding caused by differences in populations and trial designs (including differences in trial durations, comparators, randomization ratios, and semaglutide doses investigated), the proportion of people with events and the event rate per 100 patient‐years of exposure for all pooled datasets were adjusted using Cochran–Mantel–Haenszel weights.
RESEARCH IN CONTEXT
Systematic review: Accumulating preclinical and clinical evidence indicates neuroprotective effects of glucagon‐like peptide‐1 receptor agonists. The evoke and evoke+ trials are investigating the efficacy and safety of semaglutide in participants aged 55 to 85 years with early Alzheimer's disease (AD). To support these studies, an evaluation of existing background literature revealed a need to characterize the safety of semaglutide in older adults.
Interpretation: Examining adverse event (AE) data for participants aged ≥ 65 years with type 2 diabetes (T2D) and/or overweight/obesity from the PIONEER, SUSTAIN, and STEP clinical programs, the AE profile of semaglutide in older adults was similar to that seen in the overall trial populations.
Future directions: In participants with T2D and/or overweight/obesity, age ≥ 65 years did not appear to affect the safety considerations of semaglutide. This safety characterization in older adults will inform the ongoing evaluation of semaglutide in participants with early AD in the evoke and evoke+ trials.
For analysis of body weight, data were pooled for all oral semaglutide doses (3, 7, and 14 mg) and for placebo in PIONEER 1, 4, 5, and 8. Data were presented as estimated mean changes from baseline, using a mixed model for repeated measures with post‐baseline values from the on‐treatment period as dependent variables, study ID, treatment, and sex as fixed effects, and baseline weight as a covariate. Treatment, sex, and baseline weight were nested within the visit. Participants without post‐randomization measurements for body weight were not included in the analysis.
3. RESULTS
3.1. Baseline characteristics
Data were available from 3529 participants ≥ 65 years from the PIONEER (n = 1901), SUSTAIN (n = 1147), and STEP (n = 481) pools. Baseline characteristics for the overall trial population and for participants ≥ 65 years are shown in Table 1. At baseline, the mean (standard deviation [SD]) age of participants ≥ 65 years treated with semaglutide was 70.0 (4.4), 69.6 (4.0), and 69.3 (3.7) years in the PIONEER, SUSTAIN, and STEP pools, respectively. Mean (SD) body mass index (BMI) in participants ≥ 65 years treated with semaglutide in the PIONEER, SUSTAIN, and STEP pools was slightly lower than that in the overall population. Race characteristics were generally similar across the overall population and participants aged ≥ 65 years.
TABLE 1.
Demographics and baseline characteristics for the overall population and people aged ≥ 65 years in the pooled PIONEER, SUSTAIN, and STEP trials.
| Overall population | People aged ≥ 65 years | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PIONEER pool (n = 6352 participants with T2D) | SUSTAIN (n = 4807 participants with T2D) | STEP (n = 4783 participants with overweight/obesity ± T2D) | PIONEER pool (n = 1901 participants with T2D) | SUSTAIN (n = 1147 participants with T2D) | STEP (n = 481 participants with overweight/obesity ± T2D) | |||||||
| Demographic/ characteristic | OD oral semaglutide 3, 7, or 14 mg (n = 4116) | Comparator a (n = 2236) | OW sc semaglutide 0.5 or 1 mg (n = 3150) | Comparator b (n = 1657) | OW sc semaglutide 2.4 mg (n = 3,001) | Placebo (n = 1782) | OD oral semaglutide 3, 7, or 14 mg (n = 1229) | Comparator a (n = 672) | OW sc semaglutide 0.5 or 1 mg (n = 738) | Comparator b (n = 409) | OW sc semaglutide 2.4 mg (n = 301) | Placebo (n = 180) |
| Sex, female—n (%) | 1831 (44.5) | 1031 (46.1) | 1355 (43.0) | 715 (43.2) | 2128 (70.9) | 1,212 (68.0) | 553 (45.0) | 303 (45.1) | 302 (40.9) | 161 (39.4) | 188 (62.5) | 110 (61.1) |
| Age, years—mean (SD); median (range) | 58.2 (10.4) 59.0 (21.0–92.0) | 58.5 (10.3) 59.0 (18.0–86.0) | 56.6 (10.4) 57.0 (20.0–84.0) | 56.3 (10.8) 56.0 (18.0–87.0) | 47.8 (12.7) 48.0 (18.0–86.0) | 48.9 (12.1) 50.0 (18.0–82.0) | 70.0 (4.4) 69.0 (65.0–92.0) | 70.2 (4.5) 69.0 (65.0–86.0) | 69.6 (4.0) 69.0 (65.0–84.0) | 69.6 (4.1) 68.0 (65.0–87.0) | 69.3 (3.7) 69.0 (65.0–87.0) | 68.6 (3.4) 68.0 (65.0–82.0) |
| Body weight, kg—mean (SD) | 87.7 (21.4) c | 89.4 (21.1) | 87.9 (22.5) d | 89.0 (21.3) e | 102.1 (22.6) | 101.7 (22.0) | 81.4 (20.0) i | 84.2 (19.3) | 80.8 (20.4) | 81.6 (19.2) | 93.4 (19.7) | 96.6 (18.7) |
| BMI, kg/m2 – mean (SD) | 31.3 (6.5) f | 32.0 (6.4) | 31.9 (6.9) g | 32.4 (6.3) h | 36.7 (6.8) | 36.6 (6.9) | 29.7 (5.9) i | 30.4 (5.7) | 30.1 (6.3) j | 30.3 (5.6) k | 34.5 (5.8) | 35.4 (6.5) |
| Race—n (%) | ||||||||||||
| White | 2579 (62.7) | 1562 (69.9) | 1834 (58.2) | 1074 (64.8) | 2103 (70.1) | 1266 (71.0) | 779 (63.4) | 495 (73.7) | 432 (58.5) | 279 (68.2) | 218 (72.4) | 147 (81.7) |
| Black or African American | 248 (6.0) | 146 (6.5) | 171 (5.4) | 97 (5.9) | 262 (8.7) | 152 (8.5) | 53 (4.3) | 39 (5.8) | 29 (3.9) | 10 (2.4) | 15 (5.0) | 14 (7.8) |
| Asian | 1115 (27.1) | 431 (19.3) | 1072 (34.0) | 425 (25.6) | 514 (17.1) | 299 (16.8) | 362 (29.5) | 119 (17.7) | 269 (36.4) | 108 (26.4) | 61 (20.3) | 15 (8.3) |
| Other | 81 (2.0) | 42 (1.9) | 41 (1.3) | 31 (1.9) | 84 (2.8) | 48 (2.7) | 8 (0.7) | 6 (0.9) | 2 (0.3) | 2 (0.5) | 1 (0.3) | 1 (0.6) |
| Unclassified/NA | 93 (2.3) | 55 (2.5) | 32 (1.0) | 30 (1.8) | 38 (1.3) | 17 (1.0) | 26 (2.1) | 13 (1.9) | 6 (0.8) | 10 (2.4) | 4 (1.3) | 2 (1.1) |
Abbreviations: BMI, body mass index; ER, extended release; NA, not available; OD, once daily; OW, once weekly; sc, subcutaneous; SD, standard deviation; T2D, type 2 diabetes.
Comparator: sitagliptin, empagliflozin, liraglutide, dulaglutide, or placebo.
Comparator: exenatide ER, insulin glargine, sitagliptin, oral antidiabetic drug, or placebo.
n = 4115.
n = 3148.
n = 1655.
n = 4114.
n = 2942.
n = 1552.
n = 1228.
n = 662.
n = 379.
3.2. Adverse events
AEs in the overall trial populations and in participants ≥ 65 years are summarized in Table 2. The proportions of participants ≥ 65 years reporting AEs in the semaglutide arms of the PIONEER, SUSTAIN, and STEP pools were 79.6%, 73.6%, and 92.4%, respectively, compared with 75.2%, 72.0%, and 88.0% in the comparator arms (Table 2). These proportions were similar to those reported in the overall populations of these trials (Table 2). The proportions of participants ≥ 65 years with AEs leading to permanent discontinuation of semaglutide were 12.4%, 11.1%, and 9.3% in the PIONEER, SUSTAIN, and STEP pools, respectively, which were numerically higher than in the overall population (8.7%, 7.8%, and 5.7%, respectively; Table 2).
TABLE 2.
Summary of adverse events for individuals aged ≥ 65 years versus the overall populations in the pooled PIONEER, SUSTAIN, and STEP trials.
| Overall population | People aged ≥65 years | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PIONEER pool (n = 6352 participants with T2D) | SUSTAIN (n = 4807 participants with T2D) | STEP (n = 4783 participants with overweight/obesity ± T2D) | PIONEER pool (n = 1901 participants with T2D) | SUSTAIN (n = 1147 participants with T2D) | STEP (n = 481 participants with overweight/obesity ± T2D) | |||||||||||||||||||
| OD oral semaglutide 3, 7, or 14 mg (n = 4116) | Comparator a (n = 2236) | OW sc semaglutide 0.5 or 1 mg (n = 3150) | Comparator b (n = 1657) | OW sc semaglutide 2.4 mg (n = 3001) |
Placebo (n = 1782) |
OD oral semaglutide 3, 7, or 14 mg (n = 1229) | Comparator a (n = 672) | OW sc semaglutide 0.5 or 1 mg (n = 738) | Comparator b (n = 409) | OW sc semaglutide 2.4 mg (n = 301) |
Placebo (n = 180) |
|||||||||||||
| Exposure time, years | 4379 | 2335 | 2712 | 1467 | 3886 | 2295 | 1243 | 664 | 613 | 362 | 394 | 231 | ||||||||||||
| N (%) | R | N (%) | R | N (%) | R | N (%) | R | N (%) | R | N (%) | R | N (%) | R | N (%) | R | N (%) | R | N (%) | R | N (%) | R | N (%) | R | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| AEs |
3087 (74.9) |
302.2 |
1616 (73.0) |
259.0 |
2316 (73.2) |
370.8 |
1136 (68.7) |
284.4 |
2729 (90.8) |
575.1 |
1528 (86.2) |
422.0 | 979 (79.6) | 341.7 | 497 (75.2) | 268.3 | 555 (73.6) | 412.0 | 296 (72.0) | 314.0 | 277 (92.4) | 574.9 | 154 (88.0) | 393.0 |
| AEs leading to permanent treatment discontinuation |
329 (8.7) |
15.8 |
100 (4.2) |
5.8 |
240 (7.8) |
13.6 | 51 (3.0) | 5.5 |
168 (5.7) |
4.28 |
54 (3.0) |
2.3 | 142 (12.4) | 23.5 | 40 (5.9) | 9.3 | 84 (11.1) | 15.9 | 16 (3.7) | 5.1 | 28 (9.3) | 7.4 | 7 (3.3) | 2.4 |
| Serious AEs |
345 (8.6) |
12.8 |
202 (9.0) |
12.2 |
210 (7.0) |
11.1 |
95 (5.8) |
7.9 |
278 (9.3) |
10.2 |
131 (7.1) |
7.1 | 133 (11.1) | 18.0 | 78 (12.0) | 17.1 | 53 (7.0) | 12.8 | 35 (8.6) | 11.4 | 45 (15.6) | 21.5 | 26 (14.3) | 12.9 |
| GI disorders c |
1571 (39.1) |
90.1 |
540 (24.8) |
44.1 |
1335 (41.9) |
132.2 |
366 (22.0) |
50.7 |
2216 (73.4) |
254.0 |
893 (51.0) |
113.3 | 535 (44.6) | 103.9 | 152 (24.1) | 40.7 | 356 (46.4) | 157.9 | 107 (25.3) | 55.4 | 221 (73.8) | 230.6 | 82 (48.6) | 89.5 |
| Nausea d |
572 (15.4) |
21.6 |
146 (6.3) |
8.2 |
585 (19.1) |
34.5 |
108 (6.3) |
9.4 |
1,339 (44.1) |
66.0 |
353 (20.4) |
25.2 | 179 (16.4) | 22.7 | 45 (6.4) | 7.4 | 151 (20.4) | 41.2 | 23 (5.2) | 6.6 | 112 (38.6) | 60.2 | 17 (10.7) | 12.8 |
| Diarrhea d |
395 (10.1) |
13.7 |
128 (5.7) |
7.1 |
404 (12.6) |
22.7 | 94 (5.7) | 8.7 |
887 (29.2) |
42.4 |
315 (17.9) |
20.0 | 115 (10.7) | 14.1 | 31 (4.6) | 6.3 | 90 (12.0) | 27.3 | 29 (7.4) | 11.4 | 77 (26.0) | 35.2 | 29 (16.8) | 16.7 |
| Constipation d |
243 (5.9) |
7.0 | 79 (3.7) | 4.1 |
218 (6.5) |
8.2 | 44 (2.7) | 3.5 |
786 (25.8) |
26.4 |
218 (12.7) |
13.2 | 98 (7.2) | 8.7 | 25 (3.9) | 4.5 | 78 (9.0) | 12.2 | 15 (3.2) | 3.5 | 88 (28.5) | 31.7 | 20 (11.7) | 11.1 |
| Vomiting d |
255 (6.6) |
10.1 |
60 (2.8) |
3.3 |
234 (7.5) |
16.0 | 56 (3.3) | 5.2 |
692 (23.1) |
35.5 |
129 (7.6) |
9.2 | 90 (7.4) | 11.9 | 14 (1.9) | 2.1 | 62 (8.8) | 25.2 | 14 (3.5) | 4.2 | 54 (18.8) | 33.5 | 9 (6.5) | 6.6 |
Note: N is the number of participants in the safety analysis set with ≥ 1 event. % and R are the Cochran–Mantel–Haenszel‐adjusted proportion of participants with ≥ 1 event (%) and event rate per 100 person‐years of exposure (R).
Abbreviations: AE, adverse event; ER, extended release; GI, gastrointestinal; OD, once daily; OW, once weekly; sc, subcutaneous; SOC, system organ class; T2D, type 2 diabetes.
Comparator: sitagliptin, empagliflozin, liraglutide, dulaglutide, or placebo.
Comparator: exenatide ER, insulin glargine, sitagliptin, oral antidiabetic drug, or placebo.
Most common SOC in the semaglutide arm of each pooled dataset.
Four most frequent AEs in the GI SOC in the semaglutide arm of each pooled dataset.
In all three pooled datasets of participants ≥ 65 years, the most frequently reported AEs were GI disorders, occurring in 44.6% to 73.8% of participants receiving semaglutide versus 24.1% to 48.6% of participants receiving a comparator (Figure 1, Table 2). Most GI AEs were mild to moderate in severity. This mirrors the pattern observed in the overall populations of PIONEER, SUSTAIN, and STEP, in which GI AEs were also the most frequently reported AEs (39.1%–73.4% with semaglutide and 22.0%–51.0% with comparator; Table 2). Nausea was the most frequently reported GI AE with semaglutide in all trials, reported in 16.4% to 38.6% of participants aged ≥ 65 years and in 15.4% to 44.1% of participants in the overall populations of the trials (Table 2).
FIGURE 1.
Proportion of participants with GI AEs in the ≥ 65 years age group versus the overall population of each trial across the pooled PIONEER, SUSTAIN and STEP trials. Data are for the safety analysis set from the on‐treatment period. AE, adverse event; GI, gastrointestinal; OD, once daily; OW, once weekly; pts, participants; sc, subcutaneous.
3.3. Age‐based subgroup analysis
Rates of AEs, serious AEs, and GI AEs were generally similar between the ≥ 65 to 74, and ≥ 75 years subgroups across all three pooled trials. Most AEs were mild to moderate in severity across subgroups (Table 3). Nausea was the most frequently reported GI AE with semaglutide in all trials, reported in 16.3% to 38.2% of participants aged ≥ 65 to 74 years, and 18.8% to 34.7% of participants aged ≥ 75 years.
TABLE 3.
Summary of adverse events by age subgroup (≥ 65–744 and ≥ 75 years) in the pooled PIONEER, SUSTAIN, and STEP trials.
| PIONEER pool (n = 4186 participants with T2D) | SUSTAIN (n = 2825 participants with T2D) | STEP (n = 1584 participants with overweight/obesity ± T2D) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| OD oral semaglutide 3, 7, or 14 mg (n = 2705) | Comparator a (n = 1481) |
OW sc semaglutide 0.5 or 1 mg (n = 1892) |
Comparator b (n = 933) | OW sc semaglutide 2.4 mg (n = 970) | Placebo (n = 614) | |||||||
| Subgroup, n | ||||||||||||
| ≥65–74 years | 1030 | 552 | 638 | 355 | 274 | 167 | ||||||
| ≥75 years | 199 | 120 | 100 | 54 | 27 | 13 | ||||||
| N (%) | R | N (%) | R | N (%) | R | N (%) | R | N (%) | R | N (%) | R | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| AEs | ||||||||||||
| ≥65–74 years | 813 (78.9) | 344.5 | 410 (74.7) | 266.9 | 478 (73.7) | 402.3 | 259 (72.4) | 310.6 | 252 (92.6) | 576.8 | 143 (86.4) | 374.7 |
| ≥75 years | 166 (81.7) | 431.4 | 87 (74.2) | 314.9 | 77 (77.1) | 474.4 | 37 (68.4) | 288.9 | 25 (90.1) | 454.5 | 11 (85.2) | 370.1 |
| Serious AEs | ||||||||||||
| ≥65–74 years | 110 (11.0) | 18.1 | 67 (12.6) | 19.8 | 44 (6.8) | 11.9 | 31 (8.6) | 11.2 | 41 (14.3) | 21.1 | 22 (13.3) | 12.3 |
| ≥75 years | 23 (9.4) | 20.0 | 11 (8.1) | 10.0 | 9 (7.7) | 18.4 | 4 (7.2) | 10.5 | 4 (13.9) | 25.3 | 4 (33.1) | 30.0 |
| Severity | ||||||||||||
| Severe | ||||||||||||
| ≥65–74 years | 90 (9.0) | 13.6 | 47 (8.9) | 12.6 | 40 (6.9) | 14.4 | 23 (6.2) | 10.1 | 39 (14.2) | 20.2 | 18 (11.4) | 10.0 |
| ≥75 years | 14 (5.8) | 9.8 | 13 (10.0) | 12.8 | 9 (9.9) | 23.8 | 3 (5.0) | 12.5 | 3 (8.5) | 15.5 | 3 (22.2) | 28.0 |
| Moderate | ||||||||||||
| ≥65–74 years | 345 (35.8) | 88.9 | 191 (34.7) | 70.4 | 162 (27.9) | 86.9 | 95 (25.7) | 60.3 | 139 (53.0) | 141.2 | 77 (47.3) | 101.0 |
| ≥75 years | 78 (39.7) | 111.0 | 31 (25.0) | 54.5 | 33 (34.2) | 101.4 | 17 (29.5) | 79.8 | 12 (43.3) | 127.4 | 7 (55.9) | 90.5 |
| Mild | ||||||||||||
| ≥65–74 years | 717 (68.5) | 242.0 | 348 (63.0) | 183.8 | 428 (64.8) | 301.1 | 231 (64.7) | 240.1 | 236 (86.6) | 415.4 | 127 (76.9) | 263.7 |
| ≥75 years | 149 (73.5) | 310.7 | 73 (64.0) | 247.6 | 68 (68.4) | 349.2 | 32 (57.4) | 196.6 | 24 (88.1) | 311.6 | 9 (66.9) | 251.6 |
| GI disorders | ||||||||||||
| ≥65–74 years | 431 (43.0) | 101.6 | 130 (24.6) | 43.6 | 300 (45.3) | 153.2 | 95 (26.0) | 53.6 | 201 (73.1) | 227.5 | 75 (45.9) | 85.6 |
| ≥75 years | 104 (53.9) | 170.7 | 22 (20.1) | 37.9 | 56 (57.0) | 176.4 | 12 (19.0) | 59.1 | 20 (68.8) | 199.5 | 7 (48.5) | 53.5 |
| Nausea | ||||||||||||
| ≥ 65–74 years | 145 (16.3) | 22.8 | 39 (6.9) | 8.0 | 124 (19.2) | 39.0 | 20 (5.2) | 6.7 | 103 (38.2) | 56.2 | 17 (10.5) | 12.3 |
| ≥75 years | 34 (18.8) | 33.1 | 6 (6.1) | 9.7 | 27 (28.8) | 53.5 | 3 (3.5) | 3.7 | 9 (34.7) | 71.8 | 0 | 0.0 |
| Diarrhea | ||||||||||||
| ≥65–74 years | 92 (9.4) | 12.8 | 27 (4.8) | 8.3 | 77 (11.7) | 27.7 | 25 (7.3) | 9.8 | 71 (26.0) | 35.0 | 26 (15.8) | 16.2 |
| ≥75 years | 23 (14.0) | 28.1 | 4 (3.2) | 4.7 | 13 (12.4) | 18.8 | 4 (6.8) | 19.6 | 6 (17.7) | 21.3 | 3 (19.3) | 19.9 |
| Constipation | ||||||||||||
| ≥65–74 years | 73 (6.5) | 8.4 | 22 (4.2) | 5.0 | 68 (9.4) | 12.6 | 13 (3.2) | 3.4 | 80 (28.5) | 31.1 | 18 (10.9) | 10.5 |
| ≥75 years | 25 (14.1) | 20.9 | 3 (2.4) | 3.7 | 10 (10.2) | 14.1 | 2 (3.0) | 4.0 | 8 (30.6) | 29.7 | 2 (17.4) | 15.2 |
| Vomiting | ||||||||||||
| ≥65–74 years | 69 (7.0) | 10.5 | 10 (1.6) | 1.8 | 55 (8.9) | 26.5 | 14 (3.9) | 4.7 | 50 (19.2) | 36.9 | 9 (5.9) | 5.9 |
| ≥75 years | 21 (11.3) | 31.1 | 4 (4.1) | 5.0 | 7 (8.6) | 11.5 | 0 | 0.0 | 4 (18.3) | 26.5 | 0 | 0.0 |
Note: N is the number of participants in the safety analysis set with ≥ 1 event. % and R are the Cochran–Mantel–Haenszel‐adjusted proportion of participants with ≥ 1 event (%) and event rate per 100 person‐years of exposure (R).
Abbreviations: AE, adverse event; ER, extended release; GI, gastrointestinal; OD, once daily; OW, once weekly; sc, subcutaneous; T2D, type 2 diabetes.
Comparator: sitagliptin, empagliflozin, liraglutide, dulaglutide, or placebo.
Comparator: exenatide ER, insulin glargine, sitagliptin, oral antidiabetic drug, or placebo.
3.4. Changes in body weight
Changes in body weight were assessed in participants from PIONEER 1, 4, 5, and 8. In this pooled analysis, participants aged ≥ 65 years receiving semaglutide had an estimated weight loss of 3.8% at week 52, compared to 0.1% in those receiving placebo (Figure 2). In the overall trial populations, estimated weight loss with semaglutide was similar to those aged ≥ 65 years: 3.7% at week 52, compared with 0.4% at week 52 for those receiving placebo. Across all participants (those aged ≥ 65 years and the overall population), weight changes showed a tendency to plateau from week 26.
FIGURE 2.
Body weight changes with oral semaglutide and placebo in participants aged ≥ 65 years in PIONEER 1, 4, 5, and 8. The PIONEER pool for body weight analysis included participants with baseline body weight measurements (n = 765). Only participants with post‐randomization body weight measurements contributed to the analysis (n = 721). The number of participants contributing to the analysis are provided for each time point. Data are estimated mean changes from baseline, using a mixed model for repeated measures with post‐baseline values from the on‐treatment period as dependent variables, and study ID, treatment, and sex as fixed effects and baseline weight as covariate. Treatment, sex, and baseline weight are nested within the visit. Error bars are ± standard error of the mean. Numbers shown in the lower panel represent the number of participants contributing to the data. Body weight loss data included are from PIONEER 1, 4, 5, and 8, which had a placebo treatment arm for the comparisons. Data are pooled for all oral semaglutide doses (3, 7, and 14 mg) and for placebo from PIONEER 1, 4, 5, and 8. Participants in PIONEER 1 and 5 contribute up to week 26 and those in PIONEER 4 and 8 contribute up to week 52.
4. DISCUSSION
This post hoc analysis of pooled data from 3529 participants with T2D and/or overweight or obesity in 22 randomized clinical trials confirmed that safety considerations pertaining to AEs with semaglutide in participants aged ≥ 65 years are similar to those observed in the overall trial populations. These findings provide a supportive foundation for the evaluation of semaglutide in individuals with early AD in the evoke and evoke+ trials. 23 , 24
According to the prescribing information of the semaglutide formulations approved based on the PIONEER, SUSTAIN, and STEP clinical programs, no dose adjustment based on age is required for use in the relevant populations for which each formulation is indicated. 25 , 26 , 27 , 28 , 29 , 30 This is supported by observations in the PIONEER, SUSTAIN, and STEP clinical programs, in which overall safety and efficacy were not affected by baseline age, 26 , 28 , 30 and no overall differences in safety or efficacy were observed between participants aged ≥ 65 years and younger adults. 25 , 27 , 29 Furthermore, age had no effect on the pharmacokinetics of semaglutide in the PIONEER, SUSTAIN, and STEP clinical programs, for which people aged up to 92 years of age were included in PIONEER 26 and up to 86 years of age in SUSTAIN and STEP. 28 , 30
Among participants aged ≥ 65 years treated with semaglutide in the PIONEER, SUSTAIN, and STEP pools, the most frequently reported AEs were GI disorders, with ≈ 16% to 39% of participants reporting nausea and 11% to 26% reporting diarrhea, a similar proportion to that observed in the overall trial populations. In the majority of cases, GI AEs in the ≥ 65 years age group were mild to moderate in severity and dose dependent. 34 Although the timeframe of AEs was not assessed in this post hoc analysis, previously published data indicate that the proportion of participants reporting GI AEs was higher in the earlier months of semaglutide treatment during the dose‐escalation phase versus the later stages of treatment. 31 , 32 , 35 This implies that a degree of tolerance to potential GI side effects from semaglutide may have developed during treatment among those with initial GI intolerance. Permanent discontinuation rates due to AEs among participants aged ≥ 65 years in the PIONEER, SUSTAIN, and STEP pools were slightly higher than those in the overall trial populations. 31 This may reflect a lower threshold to discontinue medication due to side effects in populations aged ≥ 65 years and is a relevant finding of the current analysis. In clinical practice, this means that a flexible and personalized treatment approach may be warranted.
GI events are known to be associated with the GLP‐1RA class. 34 However, evidence from clinical trials shows that a low starting dose of semaglutide followed by gradual dose escalation reduces the risk of developing GI symptoms. 34 GI AEs in patients receiving GLP‐1RAs can also be managed through patient education on dietary changes, such as consuming smaller, more frequent meals with low‐fat and easy‐to‐digest foods. 34 In a clinical setting, the dosing of semaglutide can and should be flexible, with dose titration permitted on an individualized basis. 34 Practical clinical experience focuses on the “3 Es” of GI AE mitigation: education and explanation, escalation to an appropriate individualized dose, and effective management of side effects. 34 For example, in PIONEER 7, oral semaglutide was administered on a flexible dosing schedule with individualized adjustments to 3, 7, or 14 mg once daily, without affecting overall efficacy or safety. 36 Successful management of GI AEs using patient education, dose adjustment, and/or treatment pauses was also seen in PIONEER 6, in which most patients who had discontinued treatment due to AEs were able to resume treatment. 31 , 37 Occasionally, pharmacotherapy, such as short‐term use of anti‐emetic medications, can also be used to mitigate GI AEs during the dose‐escalation period, 34 while recognizing that the clinical evidence for this approach is relatively limited. However, if GI AEs persist and/or medication to manage GI AEs cannot be tapered down, dose reduction or temporary or permanent discontinuation of treatment may be recommended. For individuals with early AD, a holistic person‐centered management strategy that combines dose titration, tailored dietary recommendations, and involvement of care partners may help to mitigate the impact of potential GI AEs.
In general, adverse reactions to medications are more common in individuals aged ≥ 65 years, which is likely related to their greater comorbidity burden and polypharmacy, as well as changes in drug pharmacokinetics and pharmacodynamics, although these are not universally observed. 38 However, in the current analysis, AE rates with semaglutide in people aged ≥ 65 years were similar to those in the overall trial populations, and within the age‐based subgroups. Populations aged ≥ 65 years tend to be heterogeneous, with the number and type of comorbidities varying greatly between individuals. 39 Heterogeneity in health also increases with age, and many physiological functions, such as the homeostatic control of fasting glucose, 39 vary more between age‐matched individuals aged ≥ 65 years than between age‐matched individuals < 65 years. 40 A flexible and personalized approach to treatment of adults ≥ 65 years, in which the dosing of medications is adjusted based on individual tolerability, is therefore warranted. In the evoke and evoke+ trials, flexible dose adjustment of oral semaglutide is permitted to increase tolerability.
The minimum age of 65 years was chosen because it resulted in a cohort with a mean age similar to the evoke and evoke+ trials. 23 , 24 However, it is worth noting that the populations in this analysis remain distinct from those in the evoke and evoke+ trials. For example, all participants in PIONEER and SUSTAIN had T2D at baseline and in STEP, the proportion of people in the overall population with T2D at baseline was 18.4% (n = 878). These proportions are higher than those in evoke and evoke+, in which T2D was present in 11.8% (n = 218) and 15.6% (n = 304) of participants, respectively. 23 , 24 Additionally, mean baseline BMI in PIONEER (30.6 kg/m2), SUSTAIN (30.8 kg/m2), and STEP (35.3 kg/m2) was higher than in evoke and evoke+ (25.7 kg/m2). 23 , 24 Despite these differences, analysis of semaglutide safety in participants aged ≥ 65 years provides important learnings for the early AD population under investigation in the evoke and evoke+ trials. Furthermore, when available, the safety findings from evoke and evoke+ will contribute to our understanding of whether previous semaglutide experience and AE management strategies (e.g., slow titration, counseling) will support tolerability in patients aged ≥ 65 years.
Weight loss associated with semaglutide has previously been considered a beneficial effect of treatment for most patients in previous studies in T2D and obesity. In a post hoc analysis of the SUSTAIN trials (30 or 56 weeks), semaglutide significantly reduced body weight by up to 6.4 kg from baseline compared to comparators across all BMI groups. 41 Similar findings were also seen in the PIONEER trials (26, 52, or 78 weeks), in which semaglutide reduced body weight by up to 6.4 kg from baseline. 42 In addition to the AE profile analysis, we analyzed the effect of oral semaglutide versus placebo on body weight in people aged ≥ 65 years in the PIONEER 1, 4, 5, and 8 trials, as well as the body weight change in the overall population of these trials. Changes in body weight were similar in both semaglutide groups (3.7% and 3.8%) and plateaued from week 26; however, the clinical implications of this finding from the T2D population for the early AD population are unclear and beyond the scope of the current analysis. Further analysis of body weight by age subgroups was not performed due to the number of participants in each subgroup being too small for meaningful comparisons. Although semaglutide reduced body weight relative to placebo in this analysis, these effects may not be directly extrapolated to the evoke and evoke+ populations due to differences in the trial populations and trial designs. For instance, evoke and evoke+ are larger and of longer duration than PIONEER 1, 4, 5, and 8; there are differences in semaglutide dosing regimens; and, as mentioned earlier, participants in evoke and evoke+ had a lower mean BMI at baseline compared with the PIONEER studies. Furthermore, in PIONEER, lifestyle recommendations specific to patients with T2D were provided. Weight loss may be considered an undesirable effect in some people with early AD, particularly if they have a low BMI at pre‐treatment baseline, and cessation of therapy, along with evaluation of nutritional and medical status, may be required if excessive weight loss is experienced during treatment in this population. To mitigate the risk of potentially detrimental weight loss, dosing of oral semaglutide in the evoke studies is flexible, with dose titration permitted on an individualized basis. Experiences and best practices from previous semaglutide clinical programs have been shared with the evoke/evoke+ investigators, and participants in the evoke trials have also received general recommendations for eating habits that can help to mitigate problems related to weight loss (e.g., eating smaller, nutritionally dense meals at more frequently predefined times of the day and ensuring adequate protein intake).
5. CONCLUSIONS
This analysis of pooled data from the PIONEER, SUSTAIN, and STEP trial programs found that safety considerations with semaglutide in participants aged ≥ 65 years with T2D and/or overweight or obesity were similar to those observed in the overall population of each program and were consistent with those with the GLP‐1RA class. While safety considerations in participants aged ≥ 65 years were similar to the overall study populations, the AE profile of semaglutide in the early AD population remains to be elucidated. It will be of interest to determine whether prior experience, education, and semaglutide dosing flexibility will minimize the impact of AEs, particularly GI AEs, in the evoke and evoke+ trials, and to establish how these AEs, alongside the potential for weight loss, will affect the overall balance of safety and efficacy of semaglutide in individuals with early AD.
CONFLICT OF INTEREST STATEMENT
Marwan Sabbagh reports consulting for Corium, Eisai, Eli Lilly, KeifeRx, NeuroTherapia, Novo Nordisk, Prothena, Roche–Genentech, Signant Health, Synaptogenix, and T3D. Cristina Boschini, Magnus Fugger, Sune Dandanell, and Luis Rafael Solís Tarazona are employees and/or shareholders of Novo Nordisk A/S. Sharon Cohen is an employee of the Toronto Memory Program and has no financial conflicts of interest. Frank Jessen reports fees for advice and presentations for AC Immune, Biogen, Danone/Nutricia, Eisai, Grifols, Eli Lilly, Janssen, Novo Nordisk, and Roche; funding from BMBF, BZGA, DFG, DZNE, Era‐net Neuron, Horizon 2020, IMI, Innovationsfonds (GBA), and JPND; memberships for the German Association of Psychiatry (DGPPN, member of the board), German Association of Biological Psychiatry (DGBP), German Psychogeriatric Association (DGGPP), German Memory Clinic Network (DNG, Chair), and European Alzheimer‘s Disease Consortium (EADC, Chair); and served on the scientific advisory boards for German Alzheimer Association, Alzheimer Europe, and Hirnliga. Sue D. Pedersen reports consulting fees or speaking honoraria from Abbott, AstraZeneca, Bausch, Bayer, Boehringer Ingelheim, Dexcom, Eli Lilly, HLS, Janssen, Merck, Novo Nordisk, Pfizer, and Sanofi; and research studies for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Medpace, and Novo Nordisk. Vanita R. Aroda reports grants and other from Applied Therapeutics, grants and other from Corcept, grants and other from Fractyl, other from Mediflix, grants and other from Novo Nordisk, other from Pfizer, grants and other from Sanofi, grants from Eli Lilly, and other from Janssen (spouse) outside the submitted work. Author disclosures are available in the supporting information.
CONSENT STATEMENT
All participants provided informed consent.
Supporting information
Supporting Information
Supporting Information
ACKNOWLEDGMENTS
Medical writing support was provided by Diana Marouco, PhD, Casey McKeown, RVN, FdSc, and Liam Gillies, PhD, of Apollo, OPEN Health Communications, and funded by Novo Nordisk, in accordance with Good Publication Practice (GPP) guidelines (www.ismpp.org/gpp‐2022). This post hoc analysis was funded by Novo Nordisk A/S. The funder was responsible for the study concept and design, and acquisition, analysis, and interpretation of data. All authors were involved in the writing of the report, critically revised the manuscript, and were involved in the decision to submit the article.
Sabbagh M, Boschini C, Cohen S, et al. Safety considerations of semaglutide in the potential treatment of Alzheimer's disease: A pooled analysis of semaglutide in adults aged ≥ 65 years. Alzheimer's Dement. 2025;11:e70076. 10.1002/trc2.70076
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