NLA 2025: GLP-1 Therapies May Impact Cardiovascular and Renal Health Independent of Weight Loss

Glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as a cornerstone of obesity pharmacotherapy, with data demonstrating multifaceted benefits that extend beyond weight loss alone. At the 2025 National Lipid Association (NLA) Scientific Sessions, Samuel Klein, MD, a professor of medicine and nutritional science at Washington University School of Medicine in St. Louis, discussed the transformative impact of GLP-1 receptor agonists on obesity management and cardiometabolic health. During the presentation, Klein underscored the potential of GLP-1–based therapies to address a broad spectrum of obesity-related comorbidities, including type 2 diabetes, dyslipidemia, metabolic dysfunction-associated steatohepatitis (MASH), chronic kidney disease (CKD), and cardiovascular disease (CVD).¹

“This is really a time of revolutionary medications for the treatment of obesity. What we have now, the drugs that are approved, is just the beginning,” Klein said during the NLA presentation. “[These therapies] have just really expanded and exploded the field. It's really science fiction coming into the future regarding these therapies, [and specifically] these polyagonists. [However,] what I tell you right now this afternoon will probably be obsolete in a very short period of time.”¹

Reversing obesity—a complex, multi-organ system disease—has been shown to lead to improvements across a constellation of cardiometabolic abnormalities, Klein explained. Weight loss, whether achieved through lifestyle interventions, pharmacotherapy, or bariatric surgery, can improve insulin resistance, beta-cell dysfunction, prediabetes, type 2 diabetes, atherogenic dyslipidemia, MASH, obstructive sleep apnea (OSA), and CKD. However, emerging evidence is suggesting that GLP-1 receptor agonists may also exert benefits related to cardiovascular and renal outcomes independent of weight loss, according to Klein.¹

Weight Loss and Lipid Modulation

A rendering of the GLP-1 molecule. Image Credit: © Your Hand Please - stock.adobe.com

Klein highlighted pivotal trials demonstrating the impact of GLP-1 receptor agonists and dual agonists such as tirzepatide (Mounjaro; Eli Lilly), a glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 combination therapy, on body weight and lipid profiles. In the SURMOUNT-1 trial (NCT04184622), tirzepatide demonstrated dose-dependent reductions in body weight of up to 20.9% over 72 weeks, along with significant improvements in triglycerides (approximately 20% reduction) and increases in high-density lipoprotein (HDL) cholesterol.^1,2 Importantly, low-density lipoprotein (LDL) cholesterol remained largely unaffected by weight loss alone, aligning with prior evidence that LDL levels are less directly influenced by adiposity.¹

In the STEP 1 trial (NCT03548935), semaglutide (Wegovy; Novo Nordisk) led to an average weight loss of 14.9% over 68 weeks, with accompanying improvements in atherogenic lipids, particularly triglycerides and HDL cholesterol.^1,3 Klein noted that these lipid changes are clinically meaningful for patients with obesity and dyslipidemia, given the reduction in triglyceride-driven atherogenic risk.¹

Glycemic Control

Klein highlighted the STEP 2 trial (NCT03552757) and the SURPASS-2 trial (NCT03987919) as key studies evaluating the impact of semaglutide and tirzepatide on glycemic control in patients with obesity and type 2 diabetes.^1,4,5 Data from these trials showed that greater weight loss corresponded with greater reductions in hemoglobin A1c, suggesting a direct correlation between the magnitude of weight loss and glycemic improvement. According to Klein, these findings reinforce the need to consider weight-centric pharmacologic strategies when managing patients with type 2 diabetes and obesity.¹

MASH and Fibrosis

Klein also discussed emerging data on the effects of GLP-1 receptor agonists on MASH, referencing trials such as a phase 2 study (NCT03987074) investigating semaglutide and another phase 2 study (NCT04166773) investigating tirzepatide.^1,6,7 In the semaglutide trial, 59% of patients achieved MASH resolution without fibrosis worsening, and 43% showed fibrosis improvement by 1 fibrosis stage or higher. According to Klein, these beneficial effects on fibrosis was not observed in earlier studies investigating these therapies.¹

“But you can see that with significant weight loss [from] semaglutide, you have an improvement in MASH resolution in a large percentage of people, and you also have an improvement in fibrosis of 1 or more [stage] without any worsening of MASH itself,” Klein said. “So, losing weight with semaglutide improves MASH, but also reduces fibrosis.”¹

The tirzepatide trial demonstrated similar benefits, with up to 51% of patients showing MASH resolution and 47% experiencing fibrosis improvement, regardless of the degree of weight loss.¹

“Reducing weight with tirzepatide shows you the same thing—that a resolution of MASH also improves fibrosis. But… the amount of weight you lose doesn't seem to be an important determinant of improvement in fibrosis,” Klein said. “Despite having different amounts of weight loss, the fibrosive improvement is the same in people taking tirzepatide.”¹

Klein noted that while these studies suggest promising antifibrotic effects, longer-term data are needed to confirm sustained fibrosis improvement.¹

Sleep Apnea

In the SURMOUNT-OSA trial (NCT05412004), tirzepatide was observed to significantly reduce the apnea-hypopnea index (AHI) in patients with moderate to severe OSA and obesity.^1,8 Patients on tirzepatide achieved a 14% weight loss and substantial improvements in AHI, reinforcing the interconnection between obesity and sleep-disordered breathing.¹

“Tirzepatide, a GLP-1 and GIP combination [agonist], has a marked beneficial effect on sleep apnea,” Klein said. “With remarkable weight loss from tirzepatide, there is a remarkable reduction in the AHI in terms of events per hour during the night.”¹

Kidney and Cardiovascular Outcomes

Klein highlighted during his presentation that the cardio-renal protection provided by GLP-1 receptor agonists may also be independent of weight loss. He reviewed data from the FLOW trial (NCT03819153), where semaglutide reduced major kidney events—including progression to kidney failure, 50% or greater decline in estimated glomerular filtration rate, and cardiovascular death—in patients with type 2 diabetes and CKD.^1,9 Notably, semaglutide achieved these benefits with a modest 6.7% weight loss over 24 months, suggesting mechanisms beyond adiposity reduction.¹

“Some of these abnormalities seem to benefit in relationship with the amount of weight that you lose, but surprisingly, some of these end points seem to also benefit with weight loss independent effects, and so with relatively small amounts of weight loss with GLP-1 agonist therapy, you might have greater beneficial effects on CVD, as well as on CKD, where the other [end points] seem to be related mostly with weight loss directly itself.”¹

Klein also highlighted cardiovascular outcome trials, including the SELECT trial (NCT03574597) for semaglutide and the SURPASS-CVOT trial (NCT06779929) for tirzepatide.^1,10,11 In SELECT, semaglutide reduced the composite end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke in patients with established CVD without diabetes, with curves diverging as early as 6 months, despite modest weight loss. In SURPASS-CVOT, tirzepatide demonstrated reduced major cardiovascular events in patients with type 2 diabetes and established atherosclerotic CVD. The divergence in event rates occurred early, preceding maximal weight loss, again hinting at direct cardioprotective effects.¹

“Losing weight is a key therapy in people who are obese and have adverse effects of obesity,” Klein said. “If they have adverse effects of obesity, losing weight is the key to treating abnormalities associated with obesity. But it does seem that GLP-1 agonist therapy may have some additional effects in some organ systems, [such as] potentially the cardiovascular system, as well as the renal system itself.”¹

REFERENCES

1. Klein S. GLP-1s: Dual benefits in dyslipidemia and cardiometabolic health. NLA Scientific Sessions; Miami, Florida; May 29-June 1.

2. A Study of Tirzepatide (LY3298176) in Participants With Obesity or Overweight (SURMOUNT-1). Clinicaltrials.gov. Updated August 1, 2024. Accessed May 31, 2025. https://clinicaltrials.gov/study/NCT04184622?term=NCT04184622&rank=1

3. STEP 1: Research Study Investigating How Well Semaglutide Works in People Suffering From Overweight or Obesity (STEP 1). Clinicaltrials.gov. Updated November 19, 2021. Accessed May 31, 2025. https://clinicaltrials.gov/study/NCT03548935?term=NCT03548935&rank=1

4. Research Study Investigating How Well Semaglutide Works in People With Type 2 Diabetes Suffering From Overweight or Obesity (STEP 2). Clinicaltrials.gov. Updated November 9, 2021. Accessed May 31, 2025. https://clinicaltrials.gov/study/NCT03552757?term=NCT03552757&rank=1

5. A Study of Tirzepatide (LY3298176) Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants With Type 2 Diabetes (SURPASS-2). Clinicaltrials.gov. Updated February 14, 2022. Accessed May 31, 2025. https://clinicaltrials.gov/study/NCT03987919?term=NCT03987919&rank=1

6. Safety, Tolerability, and Efficacy of Monotherapy and Combination Regimens in Participants With Nonalcoholic Steatohepatitis (NASH). Clinicaltrials.gov. Updated July 15, 2021. Accessed May 31, 2025. https://clinicaltrials.gov/study/NCT03987074?term=NCT03987074&rank=1

7. A Study of Tirzepatide (LY3298176) in Participants With Nonalcoholic Steatohepatitis (NASH) (SYNERGY-NASH). Clinicaltrials.gov. Updated January 24, 2025. Accessed May 31, 2025. https://clinicaltrials.gov/study/NCT04166773?term=NCT04166773&rank=1

8. Obstructive Sleep Apnea Master Protocol GPIF: A Study of Tirzepatide (LY3298176) in Participants With Obstructive Sleep Apnea (SURMOUNT-OSA). Clinicaltrials.gov. Updated April 30, 2025. Accessed May 31, 2025. https://clinicaltrials.gov/study/NCT05412004?term=NCT05412004&rank=1

9. A Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease (FLOW). Clinicaltrials.gov. Updated March 20, 2025. Accessed May 31, 2025. https://clinicaltrials.gov/study/NCT03819153?term=NCT03819153&rank=1

10. Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT). Clinicaltrials.gov. Updated August 30, 2024. Accessed May 31, 2025. https://clinicaltrials.gov/study/NCT03574597?term=NCT03574597&rank=1

11. Emulation of the Study of Tirzepatide Compared with Dulaglutide on Major Cardiovascular Events in Participants with Type 2 Diabetes (SURPASS-CVOT). Clinicaltrials.gov. Updated January 17, 2025. Accessed May 31, 2025. https://clinicaltrials.gov/study/NCT06779929?term=SURPASS&intr=tirzepatide%20&rank=1