Understanding the mechanisms leading to weight loss could help identify potential benefits for cardiorenal health in patients with chronic kidney disease.
Glycogen-like peptide-1 receptor antagonists (GLP-1 RAs) and sodium glucose contransporter-2 (SGLT2) inhibitors may have cardioprotective effects for patients with chronic kidney disease (CKD), according to Alexander R. Chang, MD, MS, a nephrology specialist, in a session at the American Society of Nephrology (ASN) 2023 Kidney Week Annual Meeting, happening November 2 to 5 in Philadelphia, Pennsylvania. However, there are limited data on the effects of the recently approved weight loss agents for this patient population or indication.1
“There is very limited safety data in CKD,” Chang said during the session. “So, we don't simply want to just lower people's weight, we want to make their health better too.”
At least 72% of patients with CKD have a larger waist circumference; among patients with CKD, approximately 50% have clinical obesity (defined as a body mass index [BMI] of 30 or greater) and more than a quarter have severe obesity (BMI of 35 or greater).
“[So] there is substantial metabolic syndrome overlap with obesity, diabetes and CKD,” Chang explained.
The history of FDA-approved weight loss drugs is a recent one; in 1999, the FDA approved a pancreatic and gastric lipase inhibitor, orlistat (Xenical), followed by approvals in 2012 and 2014 for phentermine/topiramate-ER (Qysmia; Vivus) and naltrexone/bupropion (Contrave; Currax), respectively. All are indicated for weight loss in combination with lifestyle modifications, but none had proven benefits for cardiovascular health or CKD.
The FDA also approved a weight loss drug in the GLP-1 RA class, liraglutide 3 mg (Victoza; Novo Nordisk), in 2014, and semiglutide 2.4 mg (Wegovy; Novo Nordisk) was added to the list in 2022. Both are indicated in combination with lifestyle modifications.
SGLT2 inhibitors can reduce waist circumference and have modest weight loss effects; most of this weight loss is a reduction in visceral fat. Mechanistically, this occurs because of glycosuria, the reduction of glucose and other sugars in urine, according to the National Institutes of Health.2 Glycosuria is moderated by an increase in calories.1
And upon further analysis, “some of the magical cardiorenal protective effects [of SGLT2 inhibitors] are thought to maybe be related to it shift[ing] metabolism to a pseudo-fasting state,” Chang explained during the session.
This pseudo-fasting state works to increase the disposal of endogenous glucose production, lipid oxidation, and ketogenesis (a process during which the body burns fat, not glucose) while decreasing tissue glucose. Chang explained that SGLT2 inhibitors basically work to cause energy and dehydration stress. In effect, this can cue water and energy conserving mechanisms.
“This alters the metabolism to utilize the fatty substrates which may then go on to have cardiorenal protective effects,” Chang said.
GLP-1 RAs can reduce total adipose tissue (such as visceral and liver adipose tissues) and may slow gastric emptying as well, as observed in a study of liraglutide versus placebo, Chang said. He added that semaglutide also acts on neurological pathways because the GLP-1 RA activates neurons in the hypothalamus and hindbrain, which may result in better appetite regulation.
“And mechanism-wise, the brain is very, very important here,” Chang explained. “Appetite is central to hunger and weight.”
Current GLP-1 RA efficacy data comes from multiple trials. During STEP 1, a long-term evaluation of semaglutide versus placebo for weight loss in non-diabetic patients with overweight or obesity, more than 6 times the number of patients in the semaglutide arm lost weight compared to placebo at 68 weeks (14.9% versus 2.4%, respectively), Chang said.
The SURMOUNT-1 trial, which assessed a GLP-1 RA and gastric inhibitor peptide (GIP), tirzepatide (Mounjaro; Lilly), for weight loss in patients with overweight/obesity and weight-related complications, affirmed that GLP-1 RA-combination drugs may significantly increase fat loss (33.9% total fat mass change at 72 weeks).
It’s worth noting that drugs that also antagonize GIP, an incretin hormone secreted in the small intestine, could influence weight loss. GIP is shown to have no effect on gastric emptying and can increase bone formation and lipid storage, performing the latter without inflaming adipose tissue.
Moreover, investigators conducted the FLOW trial—an evaluation of weekly semaglutide on kidney outcomes for patients with type 2 diabetes and CKD—and stopped it at the interim analysis because semaglutide was so effective at reducing time to first occurrence of kidney failure or death from kidney failure or cardiovascular death.
There are lingering questions about the efficacy of these weight loss agents for advanced and end-stage CDK, particularly around the possibility of becoming malnourished. An increased presence of small molecule GLP-1 RAs might begin to reduce costs of them, along with dual-antagonist GLP1 RA/GIP antagonists and triple antagonists.
“Both SGLT2 inhibitors and GLP-1s in general, should be considered when indicated for the cardiorenal protective benefits,” Chang concluded.
1. Chang A. Pharmacologic Mechanisms of Weight Loss to Include SGLT2 Inhibitors and GLP1/GIP Agonists. Session. ASN 2023 Kidney Week Annual Meeting. November 2 to 5, 2023. Philadelphia, Pennsylvania.
2. Liman MNP, Jialal I. Physiology, Glycosuria. [Updated 2023 Mar 13]. StatPearls. Treasure Island (FL): StatPearls Publishing; Jan 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557441/