Liraglutide, Obesity, & PCOS
Study Background
Design
Phase III, randomized, double-blind, placebo-controlled trial
Setting
Single endocrinology/metabolism clinic in Baton Rouge, Louisiana
October 2018 – June 2021
Known disorders for bleeding irregularities and androgen excess
Diabetes
Past six months: smoking or injectable hormonal contraceptives
Past three months: anti-obesity agents
Pregnancy / lactation
Uncontrolled hypertension
Acute pancreatitis
Clinically significant disease
Steroid medications or medications that impact GI motility or carb metabolism
Methodology
Obtained baseline screening labs: AM fasting OGTT, CMP, TSH, prolactin, TT, SHBG, DHEAS, cFAI, lipid panel, beta hCG
Obtained baseline measurements:
height, body weight (BW), waist circumference (WC), hip circumference (HC)
Waist-to-Hip: WC/HC —> abdominal adiposity
Blood pressure (BP)
Body composition via DXA bone density scan
Enrolled participants received the following:
Individualized food advice at baseline by registered dietitian (RD)
Lifestyle recommendations of 30 minutes daily moderate physical activity
Randomized via block randomization method via computer-generated random numbers to subcutaneous GLP1-RA liraglutide (LIRA) 3 mg vs. visually matching placebo (PL) — dose-titration was not a part of this study
Follow-up
Mid-study evaluation at 16-18 weeks: CMP + beta-hCG, BW, BMI, WC, HC, BP
Repeat of all tests at 32 weeks
Protocol amendments due to COVID pandemic forcing site lockdown
Extended ten patient visits out by 1-2 weeks
Protocol amendment for virtual visits
Still received meds from study coordinator
Took pregnancy tests at home vs. lab
Outcome Measures
Three Primary Endpoints:
1) Relative % change in BW
2) Proportion of patients who lost ≥ 5% BW
3) Change in bioavailable testosterone (per Free Androgen Index)
Numerous secondary endpoints: absolute change in BW, WC, BMI, total testosterone, DHEAS, menstrual frequency, fasting blood glucose, MBG during an OGTT, surrogate measures of insulin action (HOMA-IR, SIOGTT, IGI/HOMA), lipids, TRG/HDL-C ratio, BP, and body composition via DXA
Safety assessed in all patients who received ≥ 1 dose study drug
Statistics
continuous variables normality of distribution: Kolmogorov-Smirnov test
quantitative variables: mean and std error of mean (SEM)
continuous between group differences: SS / drug treatments repeated-measures ANOVA
Baseline comparisons, % change continuous variables: unpaired student t-tests
Frequency of achieving target BW reduction: chi-square tests
Effect of missing data in ITT: multiple imputation, assuming
missing-at-random
Stat sig defined at p ≤0.01 to reduce Type I (false +) error probability
Results
92 screened 🡪—> 82 randomized —>🡪 67 included in analysis (44 LIRA, 23 PL)
Median follow-up = 32 weeks
82% treatment adherence (11 LIRA vs. 4 PL dropouts)
Equal distribution by race: white 67%, black 33%
Similar mean age in years: LIRA 31 ± 0.9 vs. PL 32 ± 1.2
Similar in anthropometric, hormonal, glycemic, and cardiometabolic parameters
Anthropometric DXA results:
Primary Endpoint: 57% LIRA vs. 22% PL had ≥ 5% loss in BW; p = 0.009
absolute BW (p=0.002) and BMI (p=0.001) from first to last visit significantly decreased with LIRA 3 mg
Greater decrease in total fat mass in LIRA; p = 0.028
Greater AGR reduction in LIRA; p = 0.034
No significant changes in LBM
Hormones:
Primary endpoint: mean FAI showed decrease in LIRA vs. PL; p = 0.006
No significant changes in TT
More regular menses with LIRA vs. PL; p = 0.0001
Glucose:
Improved OGTT excursion on LIRA vs. PL; p = 0.009
Fasting insulin sensitivity per HOMA-IR improved on LIRA; p = 0.035
Cardiac
TC, HDL, LDL not affected
TG and TG/ HDL ratio reduced; p = 0.016 and p = 0.028
SBP and DBP not affected
Safety
More nausea in LIRA (25.5%) vs. PL (11%)
Injection-site reactions detected in LIRA (5.5%) vs. PL (0%)
Additional LIRA AEs: headache, diarrhea, vomiting, and constipation
Two LIRA dropouts due to pregnancy / full-term healthy deliveries
Authors’ Thoughts
In premenopausal women with PCOS and obesity, short-term LIRA reduces BW and androgenicity and improves cardiometabolic parameters
This Pharmacist’s Thoughts
(+) randomized, double-blind, placebo-controlled, improvised well with COVID, thoughtful statistical analysis, 33% patients African-American
(-) single-site, lack of PROs, surrogate markers for insulin sensitivity, lifestyle changes encouraged but not assessed
Conclusions
This well-designed investigator-initiated trial opens the path for increased use of liraglutide in women with obesity and PCOS.
Resources
Elkind-Hirsch KE, Chappell N, Shaler D, Storment J, Bellanger D. Liraglutide 3 mg on weight, body composition, and hormonal and metabolic parameters in women with obesity and polycystic ovary syndrome: a randomized placebo-controlled-phase 3 study. Fertil Steril. 2022;118(2):371-381. doi:10.1016/j.fertnstert.2022.04.027
Gill L, Mackey S. Obstetrician-Gynecologists' Strategies for Patient Initiation and Maintenance of Antiobesity Treatment with Glucagon-Like Peptide-1 Receptor Agonists. J Womens Health (Larchmt). 2021;30(7):1016-1027. doi:10.1089/jwh.2020.8683
Latif W, Lambrinos KJ, Rodriguez R. Compare And Contrast the Glucagon-like Peptide-1 Receptor Agonists (GLP1RAs) [Updated 2022 Mar 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK572151/
Pi-Sunyer X, Astrup A, Fujioka K, et al. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. N Engl J Med. 2015;373(1):11-22. doi:10.1056/NEJMoa1411892
Saxenda (liraglutide) [prescribing information]. Plainsboro, NJ: Novo Nordisk; 2022.
