Losing Weight before IVF

This multi-center, randomized, placebo-controlled, double-blinded trial is the first to compare live birth rates in overweight or obese women who received the weight loss drug orlistat before IVF with embryo transfer (IVF-ET).

Study Background

WHAT

• Will taking orlistat for 4-12 weeks before IVF-ET improve rates of live birth?

• Hypothesis: orlistat will improve the birth rate by 10% in overweight or obese women

WHY

• Obesity increases risks of miscarriages and poor IVF outcomes

• Weight loss improves ovulation and pregnancy rates

• Lack of research looking at impact of pharmacological-weight loss in infertility patients

WHERE

• 19 fertility centers in China

WHEN

• July 2017-Jan 2018

WHO

• 888 women

  • ages 20-40 years

  • Body Mass Index (BMI) >24

    • BMI 25-29 considered overweight, BMI >29 considered obese

  • scheduled to use IVF or intracytoplasmic sperm injection (ICSI)

    • included those being treated for pelvic factor, ovulatory issues, male factor, or unexplained infertility

    • excluded women with >2 previous IVF/ICSI cycles without pregnancy, uterine abnormalities, malabsorption syndrome, cholestasis, active hypothyroidism, hepatic or renal impairment, or already on weight-loss medication

HOW

• Randomization

  • 1:1 orlistat to placebo

  • all the patients, the study investigators, and their staff did not know who was receiving orlistat vs. placebo

• Orlistat 120 mg by mouth three times daily (or indistinguishable placebo)

  • Returned at 4 week intervals to record drug usage, weight change, side effects

  • Permitted self-reporting of drug adherence

• Supplements

  • Rx for daily multivitamin

  • Advice for helpful physical exercises + low-fat diet

• Individualized Protocols for Controlled Ovarian Hyperstimulation (COH)

• Fertilization by IVF or ICSI per clinic practice

• Transfer of fresh embryos prioritized > frozen embryo transfer

• Transfer of 1-3 embryos on Day 3 or Day 5

• Luteal phase support started on day of oocyte retrieval until 10 weeks gestation

• Telephone interviews for follow-up at 12, 28, 32 weeks pregnancy, delivery, 6 weeks post-partum

• Pregnancy and neonatal complications found through medical records

Statistics

• 80% power for 10% difference between-groups in live birth rates, p 0.05

• Medication compliance defined as 66% of tablets consumed in appropriate time interval (some women skipped one meal per day)

  Results

• 888 female participants = 439 orlistat, 438 placebo; 88% completed IVF in each group

• No significant differences between groups in live births, conception, pregnancy, or miscarriage rates between groups

• Similar results in intention-to-treat and per-protocol analyses

• Average weight loss 2.5kg in orlistat vs. 1.2kg in placebo (p = 0.005)

Study Authors’ Thoughts

(+) RCT looking at pharmacologic intervention pre-IVF to improve LBR in overweight/obese, powered to detect LBR as primary outcome

(-) substantial subject drop-out, lower fresh ET than expected—> should have considered alternate outcome of “live birth per transfer”, 20% risk of type 2 error (false negative), non-standardized lifestyle interventions, variable duration of intervention

This Pharmacist’s Thoughts

(+) reporting on weight-loss drug that is well characterized and marketed over-the-counter in many countries

(-) concomitant medications unclear, should have considered administering lower orlistat dose for increased tolerability

Conclusions

Based on this study, using orlistat to lose weight and to improve rates of live birth prior to IVF-ET is not recommended. Additional studies looking at longer term use of more tolerable weight loss drugs may yield different results.

Resources

Anderson JW. Orlistat for the management of overweight individuals and obesity: a review of potential for the 60-mg, over-the-counter dosage. Expert Opin Pharmacother. 2007;8(11):1733-1742. doi:10.1517/14656566.8.11.1733

Best D, Avenell A, Bhattacharya S. How effective are weight-loss interventions for improving fertility in women and men who are overweight or obese? A systematic review and meta-analysis of the evidence. Hum Reprod Update. 2017;23(6):681-705. doi:10.1093/humupd/dmx027

Gorgojo-Martínez JJ, Basagoiti-Carreño B, Sanz-Velasco A, Serrano-Moreno C, Almodóvar-Ruiz F. Effectiveness and tolerability of orlistat and liraglutide in patients with obesity in a real-world setting: The XENSOR Study. Int J Clin Pract. 2019;73(11):e13399. doi:10.1111/ijcp.13399

Li J, Wang Z, Wei D, et al. Effect of preconceptional orlistat treatment on in-vitro fertilization outcome in overweight/obese women: study protocol for a randomized controlled trial. Trials. 2018;19(1):391. Published 2018 Jul 18. doi:10.1186/s13063-018-2780-7

Practice Committee of the American Society for Reproductive Medicine. Electronic address: asrm@asrm.org. Obesity and reproduction: a committee opinion [published online ahead of print, 2021 Sep 25]. Fertil Steril. 2021;S0015-0282(21)01941-5. doi:10.1016/j.fertnstert.2021.08.018

Roche Laboratories Inc.. Xenical (orlistat) [package insert]. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020766s035lbl.pdfRevised January 2019. Accessed October 17, 2021.

Wang Z, Zhao J, Ma X, et al. Effect of Orlistat on Live Birth Rate in Overweight or Obese Women Undergoing IVF-ET: A Randomized Clinical Trial. J Clin Endocrinol Metab. 2021;106(9):e3533-e3545. doi:10.1210/clinem/dgab340

World Health Organization. Body mass index - BMI. Accessed October 18, 2021. https://www.euro.who.int/en/health-topics/disease-prevention/nutrition/a-healthy-lifestyle/body-mass-index-bmi