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Occurrence of Gastrointestinal Adverse Events Upon GLP-1 Receptor Agonist Initia
Occurrence of Gastrointestinal Adverse Events Upon GLP-1 Receptor Agonist Initia
LEADER 1.1
0.4
s.c. liraglutide LEADER Concomitant
3.6
1.8 mg 3.4 metformin
– +
3.7
2.1
Placebo
PIONEER 6 GLP-1RA
17.8
Comparison of 10.5
PIONEER 6 gastrointestinal adverse 19.2
oral semaglutide events during SUSTAIN 6 18.0
14 mg GLP-1RA initiation 1.0-mg dose 40.3
37.6
and titration
18.3
in participants SUSTAIN 6 17.2
(N=16,996) 0.5-mg dose
SUSTAIN 6 with (76%) and 28.9
37.0
STEP 2 STEP 2
2.4-mg dose
17.8
46.7
s.c. semaglutide 44.1
1.0 and 2.4 mg
0 10 20 30 40 50 60
Proportion (%)
LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; STEP 2, Semaglutide Treatment Effect in People with Obesity;
SUSTAIN 6, Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes; PIONEER 6, Peptide Innovation for
Early Diabetes Treatment.
Concomitant metformin did not increase the frequency (primary endpoint) or severity of GI AEs during GLP-1RA initiation
or titration, and concomitant metformin did not increase GLP-1RA discontinuation
ARTICLE HIGHLIGHTS
BRIEF REPORT
OBJECTIVE
To assess the impact of concomitant metformin use on gastrointestinal adverse
events during the initiation and titration of a glucagon-like peptide 1 receptor agonist
(GLP-1RA).
low dose and titrated to minimize the oc- and titration until the maintenance dose Wald test was used to test for significance
currence of GI symptoms. Still, most was achieved. We chose this period be- of the interaction within each trial.
treatment-related GI adverse events occur cause GI adverse events commonly start
during the dose titration period. Few anal- during GLP-1RA initiation, continue through RESULTS
yses have examined whether concomitant titration, and resolve after the maintenance Of 16,996 participants in these four trials,
metformin use exacerbates GLP-1RA– dose is reached (9). We defined the obser- 12,928 (76%) were treated with metformin
associated GI symptoms, and real-world vation window as the time from GLP-1RA at baseline. STEP 2 had a higher proportion
data and meta-analyses of randomized initiation until the day of the last titration of metformin users (89.6%) among all trials
controlled trials are inconsistent (1–3). Re- plus four half-lives of the GLP1-RA (esti-
(LEADER: 74.7%, SUSTAIN 6: 73.2%, and
gardless, some experts suggest metformin mated time to achieve final steady state).
PIONEER 6: 77.3%). Baseline characteristics
discontinuation or dose reduction during The observation windows are shown in
are provided in Table 2 and were similar
GLP-1RA initiation (4). The purpose of this Table 1. LEADER evaluated liraglutide (half-
between treatment arms within the trials,
Table 2—Demographics
LEADER STEP 2 SUSTAIN 6 PIONEER 6
Metformin No metformin Metformin No metformin Metformin No metformin Metformin No metformin
Male, n (%) 4,540 (65.2) 1,450 (61.6) 533 (48.9) 60 (50.8) 1,463 (60.7) 531 (60.6) 1,693 (68.8) 482 (66.9)
Age, years 63.9 (7.0) 65.4 (7.8) 55.3 (10.5) 55.6 (11.6) 63.9 (7.0) 66.4 (8.0) 66.4 (8.0) 67.8 (7.6)
Duration of duration, years 12.5 (7.7) 13.9 (8.9) 8.2 (6.1) 7.0 (5.7) 13.3 (7.7) 15.5 (8.9) 14.3 (8.2) 16.8 (9.5)
2
BMI, kg/m 32.5 (6.1) 32.6 (6.9) 35.7 (6.3) 36.2 (6.3) 32.8 (5.9) 32.9 (7.0) 31.9 (6.3) 33.6 (7.0)
HbA1c, % 8.6 (1.5) 8.9 (1.6) 8.1 (0.8) 8.0 (0.7) 8.6 (1.4) 8.9 (1.5) 8.1 (1.6) 8.3 (1.6)
eGFR, mL/min/1.73 m2 83.0 (19.2) 67.6 (25.8) 95.7 (18.7) 92.9 (16.9) 81.3 (19.4) 61.0 (25.1) 77.5 (19.4) 62.9 (22.1)
1RA initiation and titration observation diarrhea (14). Whether metformin should associates with lower odds of GI adverse
window (Supplementary Table 5). be paused to promote successful GLP-1RA events or drug discontinuation among pa-
initiation remains an important clinical tients treated with GLP-1RA (2).
CONCLUSIONS question. In this post hoc analysis of four The reasons for this finding are likely
GI adverse events are the most prevalent large GLP-1RA trials in type 2 diabetes, we multifactorial but may be due to in-
adverse effects associated with GLP-1RAs. demonstrate that concomitant metformin creased baseline or susceptibility to GI
use during GLP-1RA initiation does not as- symptoms. In LEADER, SUSTAIN 6, and
Although largely temporary and mild-
sociate with increased risk or severity of GI PIONEER 6, people who were not treated
to-moderate in severity, GI adverse events
adverse events or premature discontinua- with metformin had lower kidney func-
lead to discontinuation of GLP-1RAs both
tion of study product. We did not evaluate tion. As such, people without concomi-
in clinical trial programs and in the real
simultaneous initiation of metformin and tant metformin treatment may reflect a
world (5–8,10). Factors that modify the
GLP-1RA. sicker population with a greater symptom
risk or severity of GI symptoms are not Interestingly, in every study, the percent- burden. Nonetheless, similar findings were
well established, but practical ways to mit- age of participants experiencing any GI seen in STEP 2, where the eGFR was equiv-
igate GI adverse events and prevent GLP- adverse event was numerically higher in alent between metformin users and non-
1RA discontinuation are needed given the participants without concomitant metfor- users. As metformin was considered the
glycemic, weight loss, and cardiovascular min treatment, irrespective of randomiza- single first-line pharmacological therapy for
benefits of GLP-1RAs that have made them tion to GLP-1RA or placebo. We also found type 2 diabetes when all four studies were
a potential first-line therapy for type 2 dia- that of those who experienced GI adverse enrolling (15), it is conceivable that partici-
betes and obesity (11–13). Although the events, a higher percentage of participants pants who did not tolerate treatment with
mechanisms for GI intolerance are different, without concomitant metformin treatment metformin may be more susceptible to GI
reasonable clinical concern exists that discontinued the study product in both adverse events independent of the study
metformin use may exacerbate GLP-1RA– treatment arms across all four studies.These product. Techniques for mitigating GLP-
induced GI symptoms, as metformin alone data are consistent with real-world evidence 1RA–induced GI symptoms, such as in-
can cause abdominal pain, cramps, and from the U.K. suggesting metformin use depth counseling and slow titration (4,9),
n = number of subjects with event; N = total number of subjects exposed. *Differences in adverse event data collection explain the lower
number of adverse events in the LEADER and PIONEER-6 trials. STEP 2 and SUSTAIN evaluated two doses of semaglutide, which were ana-
lyzed separately. Doses are indicated in the table.
4 Combined Metformin-GLP1RA Use and GI Symptoms Diabetes Care
Table 4—Participants with any GI adverse event during the observation window treated with and without metformin who
discontinued study product at any time during the trial
GLP-1RA Placebo
Trial* Total n/N (%) Metformin n/N (%) No metformin n/N (%) Metformin n/N (%) No metformin n/N (%)
LEADER** 103/188 (54.8) 62/117 (53.0) 29/43 (67.4) 7/15 (46.7) 5/13 (38.5)
STEP 2
1.0 mg semaglutide 38/254 (15.0) 24/164 (14.6) 4/14 (28.6) 5/63 (7.9) 5/13 (38.5)
2.4 mg semaglutide 44/319 (13.8) 28/204 (13.7) 2/22 (9.1) 8/78 (10.3) 6/15 (40.0)
SUSTAIN 6
0.5 mg semaglutide 156/543 (28.7) 53/178 (29.8) 29/77 (37.7) 52/207 (25.1) 22/81 (27.2)
1.0 mg semaglutide 182/615 (29.6) 76/223 (34.1) 31/91 (34.1) 52/216 (24.1) 23/85 (27.1)
n = number of subjects with event; N = total number of subjects exposed with a GI adverse event within the observation window.
*Differences in adverse event data collection explain the lower number of adverse events in the LEADER and PIONEER 6 trials.
**Discontinuation in the LEADER trial is different from the other trials as it only captures drug withdrawn due to an adverse event. STEP 2
and SUSTAIN 6 evaluated two doses of semaglutide, which were analyzed separately. Doses are indicated in the table.
may be necessary in individuals with a symptoms is necessary in all patients, in- trials studying glucagon-like peptide-1 receptor
low eGFR or those who did not tolerate creased counseling or slowed titration agonists: a systematic analysis of published clinical
trials. Diabetes Obes Metab 2017;19:336–347
metformin. may be necessary in metformin nonusers. 2. Thong KY, Gupta PS, Blann AD, Ryder RE. The
In all studies, we compared active influence of age and metformin treatment status
treatment to placebo within the two met- on reported gastrointestinal side effects with
formin subgroups (metformin users and Funding. K.R.K. is supported by the University liraglutide treatment in type 2 diabetes. Diabetes
of North Carolina Department of Medicine and Res Clin Pract 2015;109:124–129
metformin nonusers) and demonstrated 3. Wu H, Lu Z, Chen R, et al. Factors associated
School of Medicine Physician Scientist Training
no statistical difference in three trials. Al- Program. K.K.B.C. is partly funded by an Innova- with gastrointestinal side effects after liraglutide
though there were few GI adverse events tion Fund Denmark grant. treatment for type 2 diabetes. Front Endocrinol
within the short observation window of Duality of Interest. K.R.K. has received personal (Lausanne) 2023;14:1098032
compensation from Novo Nordisk for consulta- 4. Gorgojo-Martınez JJ, Mezquita-Raya P,
liraglutide (16 days) and a numerically
tion. I.L. received research funding (paid to insti- Carretero-G omez J, et al. Clinical recommendations
higher percentage of GI adverse events in to manage gastrointestinal adverse events in
tution) from Novo Nordisk, Sanofi, Merck, Pfizer,
metformin nonusers, the analysis sug- Mylan, and Boehringer Ingelheim, and received patients treated with Glp-1 receptor agonists: a
gested a statistically significant increase in advisory/consulting fees and/or other support multidisciplinary expert consensus. J Clin Med
GI adverse events in participants treated from Novo Nordisk, Eli Lilly, Sanofi, AstraZeneca, 2022;12:145
Boehringer Ingelheim, Janssen, Intercept, Intarcia, 5. Davies M, Færch L, Jeppesen OK, et al.; STEP 2
with metformin. The marked difference in Study Group. Semaglutide 2·4 mg once a week in
TargetPharma, Merck, Pfizer, Novartis, GI Dynam-
pharmacokinetics between liraglutide and adults with overweight or obesity, and type 2
ics, Mylan, Mannkind, Valeritas, Carmot, Zealand
semaglutide could account for this differ- Pharma, Shionogi, Mediflix, and Bayer. E.F. is a diabetes (STEP 2): a randomised, double-blind,
ence. However, it is more likely that the former employee of Novo Nordisk. K.K.B.C., S.O., double-dummy, placebo-controlled, phase 3 trial.
Lancet 2021;397:971–984
statistical significance of this finding is due and T.J.A. are employees of Novo Nordisk. No other
6. Husain M, Birkenfeld AL, Donsmark M, et al.;
to the small sample size resulting from potential conflicts of interest relevant to this article
PIONEER 6 Investigators. Oral semaglutide and
were reported.
the method of adverse event collection. cardiovascular outcomes in patients with type 2
Author Contributions. K.R.K., K.K.B.C., E.F., and
Accordingly, statistical significance was not diabetes. N Engl J Med 2019;381:841–851
I.L. conceptualized the study design. K.R.K. and
observed in the sensitivity analysis that in- 7. Marso SP, Bain SC, Consoli A, et al.; SUSTAIN-6
I.L. drafted the manuscript. K.K.B.C., E.F., and S.O.
Investigators. Semaglutide and cardiovascular
cluded more adverse events by extending conducted the analyses. T.A. contributed to data
outcomes in patients with type 2 diabetes. N Engl
the observation to 140 days. Consistently, quality assurance and design and provided
J Med 2016;375:1834–1844
analysis expertise. All authors contributed to
although a prior meta-analysis suggested manuscript review and editing and clinical sub-
8. Marso SP, Daniels GH, Brown-Frandsen K,
statistically significant increased GI-adverse et al.; LEADER Steering Committee; LEADER Trial
ject matter expertise. I.L. contributed to regu-
Investigators. Liraglutide and cardiovascular
events in people treated with concomitant lar oversight and communications. E.F. and I.L.
outcomes in type 2 diabetes. N Engl J Med 2016;
metformin, this was largely mediated by are guarantors of this work and, as such, had
375:311–322
short-acting GLP-1RAs (exenatide, lixisena- full access to all of the data in the study and 9. Wharton S, Davies M, Dicker D, et al. Managing
take responsibility for the integrity of the data the gastrointestinal side effects of GLP-1 receptor
tide), as no statistically significant increase and the accuracy of the data analysis. agonists in obesity: recommendations for clinical
in GI adverse events was seen with longer- Prior Presentation. Parts of this study were practice. Postgrad Med 2022;134:14–19
acting GLP-1RAs like liraglutide (1) . presented in abstract form at 83rd Scientific Ses- 10. Sikirica MV, Martin AA, Wood R, Leith A,
Taken together, these data indicate sions of the American Diabetes Association, San Piercy J, Higgins V. Reasons for discontinuation of
Diego, CA, 23–26 June 2023.
that concomitant metformin use does not GLP1 receptor agonists: data from a real-world
exacerbate GLP-1RA–induced GI symp- cross-sectional survey of physicians and their
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