Obesity contributes (directly or indirectly) to a significant portion of chronic kidney disease (CKD), increasing the risk of adverse cardiometabolic outcomes in people with CKD. Fortunately, obesity therapy has advanced rapidly in the last decade with the advent of incretin-based therapies, which not only help patients to lose weight but also to reduce the risk of cardiovascular disease.
Two recent phase 2 studies published in The New England Journal of Medicine (NEJM) shed light on the potential to change the landscape of nephrology care with incretin-based treatments (1, 2). Both studies included adults with obesity or overweight and with a weight-related condition but not with diabetes mellitus. The first study tested multiple dosages of an oral glucagon-like peptide 1 receptor agonist (GLP1ra), orforglipron (1). The highest dose of orforglipron caused a mean 12.6% body weight decrease at 26 weeks (primary outcome) and a 15% decrease at 36 weeks (secondary outcome), significantly greater than the weight loss observed at currently approved dosages of the only other oral GLP1ra, semaglutide. However, the higher-dose semaglutide has recently been shown to produce a similar 15% weight loss (3). Mean systolic blood pressure (SBP) improved by 10.5 mm Hg in the high-dose orforglipron group compared with 1.8 mm Hg in the control group. The second study examined retatrutide, an injectable glucose-dependent insulinotropic polypeptide/GLP1/glucagon receptor triple agonist given weekly (2). The highest-dose group exhibited weight loss of 18% at 24 weeks and 24% at 48 weeks. Of the participants, 41% discontinued at least one blood pressure medication, with a significant decrease in SBP of 11 mm Hg compared with the control group's 3.4 mm Hg decrease. It should be noted that no patients with advanced CKD (estimated glomerular filtration rate <30 mL/min/m2) were included in these studies.
…Two recent studies shed light on the potential to change the landscape of nephrology care with incretin-based treatments.
Although incretin-based therapies have proven cardiovascular benefits, no study has conclusively demonstrated reduction in adverse kidney events as a primary outcome. The FLOW study of semaglutide in patients with type 2 diabetes and CKD should change that, however, and will help to elucidate a reduction in adverse kidney events, as the primary outcome is a composite of kidney outcomes (4).
Despite limitations, the implications for nephrologists are clear. Cardiovascular disease remains the leading cause of death for patients with CKD, and comprehensive cardiometabolic care for our patients in the future is almost certain to include effective lifestyle and pharmacologic management of obesity. Treating obesity will benefit patients with CKD by helping control hypertension and diabetes, reducing the risk of heart attacks and strokes, and helping patients previously excluded from waitlists become eligible for kidney transplant. However, patients will see these benefits only if clinicians are prepared to implement the array of novel, effective tools at our disposal. The studies published in NEJM offer a glimpse into the future of obesity management, with safe and effective oral options and medical therapy with efficacy rivaling that of bariatric surgery (Figure 1) (1, 2). With the advent of new therapies, the future for nephrology patients and the field has never been brighter.
GLP1ra orforglipron and injectable triple agonist retatrutide
Citation: Kidney News 15, 9
Daily oral GLP1ra orforglipron and weekly injectable triple agonist retatrutide are both efficacious and safe in phase 2 trials published in NEJM. The highest doses in each trial resulted in a mean weight loss of >10% and for retatrutide, over 20%. Dark bars, primary endpoint; light bars, secondary endpoints. Figure created with BioRender. Data adapted from Wharton et al. (1) and Jastreboff et al. (2).References
- 1.↑
Wharton S, et al.; GZGI Investigators. Daily oral GLP-1 receptor agonist orforglipron for adults with obesity. N Engl J Med (published online ahead of print June 23, 2023). doi: 10.1056/NEJMoa2302392; https://www.nejm.org/doi/10.1056/NEJMoa2302392
- 2.↑
Jastreboff AM, et al.; Retatrutide Phase 2 Obesity Trial Investigators. Triple-hormone-receptor agonist retatrutide for obesity—a phase 2 trial. N Engl J Med 2023; 389: 514–526. doi: 10.1056/NEJMoa2301972
- 3.↑
Knop FK, et al.; OASIS 1 Investigators. Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (published online ahead of print June 23, 2023). doi: 10.1016/S0140-6736(23)01185-6; https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01185-6/fulltext
- 4.↑
Perkovic V, et al. FC 123: Baseline characteristics of the Flow trial population: Kidney outcomes trial with once-weekly semaglutide in people with type 2 diabetes and chronic kidney disease. Nephrol Dial Transplant 2022; 37 (Suppl 3). https://academic.oup.com/ndt/article/37/Supplement_3/gfac126.002/6578114?login=true