PHILADELPHIA – New classes of weight loss medications like GLP-1 receptor agonists (GLP-1 RAs) and sodium glucose co-transporter 2 (SGLT2) inhibitors could potentially have cardioprotective effects for patients with chronic kidney disease (CKD), but there is still limited data on their efficacy and safety in this population, particularly those with advanced or end-stage CKD, according to a nephrology expert.
In a presentation at the American Society of Nephrology (ASN) 2023 Kidney Week Annual Meeting on November 2, Alexander R. Chang, MD, MS, a specialist in nephrology, noted that while these newer drugs approved for weight loss show promise, more research is needed before they can be broadly recommended for patients with significant CKD.
“There is very limited safety data in CKD,” Chang said. “So we don’t simply want to just lower people’s weight, we want to make their health better too.”
High Rates of Obesity Among CKD Patients
Chang pointed out that at least 72% of patients with CKD have a larger waist circumference, which is associated with metabolic disorders. Among the CKD population, approximately 50% have clinical obesity, defined as a body mass index (BMI) of 30 or greater, and more than a quarter have severe obesity with a BMI of 35 or greater.
“So there is substantial metabolic syndrome overlap with obesity, diabetes and CKD,” Chang said.
Given these high rates, there has been interest in whether weight loss treatments could provide benefits beyond just weight reduction in this group.
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Recent Approvals of Novel Weight Loss Drugs
The FDA has approved several new classes of weight loss medications over the past two decades after previously having limited options available.
In 1999, the first modern weight loss drug was approved – orlistat (Xenical), a pancreatic and gastric lipase inhibitor. This was followed in 2012 by the approval of the combination drug phentermine/topiramate ER (Qysmia; Vivus) and then naltrexone/bupropion ER (Contrave; Currax) in 2014. All three are indicated along with lifestyle changes for chronic weight management.
More recently, the incretin-based GLP-1 RAs liraglutide 3 mg (Victoza; Novo Nordisk) and semaglutide 2.4 mg (Wegovy; Novo Nordisk) were approved specifically for weight loss in 2014 and 2022, respectively.
SGLT2 Inhibitors Also Have Modest Weight Loss Effects
In addition to the newer weight loss agents, SGLT2 inhibitors used for type 2 diabetes also have more modest effects on weight. These drugs reduce absorption of glucose in the kidneys leading to excretion of glucose in the urine (glycosuria).
This glycosuria results in lower circulating glucose and a reduction in calories, leading to some weight loss, according to the National Institutes of Health.
Analyses have found the weight reduction with SGLT2 inhibitors is primarily a loss of visceral fat.
As Chang explained, some of the cardiorenal protective effects of SGLT2 inhibitors are thought to be related to the drugs inducing a “pseudo-fasting state” by increasing lipid oxidation and ketogenesis.
This shift in metabolism away from glucose utilization may trigger beneficial adaptations.
GLP-1 RAs May Reduce Adipose Tissue, Slow Gastric Emptying
According to Chang, GLP-1 RAs can reduce total adipose tissue, including visceral and liver fat. They also slow gastric emptying which contributes to weight loss.
Additionally, some GLP-1 RAs like semaglutide appear to act on neurons in the hypothalamus and hindbrain which regulate appetite.
“Appetite is central to hunger and weight,” Chang noted.
Efficacy Demonstrated in Several Major Trials
Data demonstrating significant efficacy of newer GLP-1 RAs comes from several large trials.
In the STEP 1 trial evaluating semaglutide for weight loss in non-diabetic individuals, over 14% of patients on semaglutide lost weight compared to only 2.4% on placebo after 68 weeks.
The SURMOUNT-1 study assessed a combination GLP-1 RA/GIP inhibitor called tirzepatide (Mounjaro) in obese patients. At 72 weeks, those on tirzepatide had 33.9% reduction in total fat mass.
Another major trial, FLOW, evaluated semaglutide on kidney outcomes in type 2 diabetes. It was stopped early when semaglutide was found to significantly reduce the risk of kidney failure and cardiovascular death.
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Questions Remain About Safety, Efficacy in Advanced CKD
While these new agents show clear benefits for weight loss and cardiorenal protection in some groups, Chang emphasized there are still unanswered questions about their safety and efficacy specifically in patients with more advanced CKD.
In particular, there are concerns that aggressive weight loss could lead to malnutrition in patients with end-stage renal disease who often already suffer from protein energy wasting. More data is needed to determine if benefits outweigh potential risks in this group.
There is also a need for more information on appropriate dosing of drugs like GLP-1 RAs that require renal clearance in advanced CKD.
Looking Ahead
Moving forward, the introduction of oral and small molecule versions of GLP-1 RAs could help reduce costs and improve accessibility of these therapies.
Combination drugs like GLP-1 RA/GIP inhibitors may also enhance weight loss effects. Further research on triple hormone antagonists is underway as well.
But overall, Chang said both SGLT2 inhibitors and GLP-1 RAs should be considered in CKD when clinically indicated for their potential cardiorenal protective effects. However, more evidence is still required before these agents can be recommended specifically for weight loss in patients with advanced chronic kidney disease.
