Obesity medications can tackle metabolic cardiorenal disease
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The effects of SGLT2 inhibitors on the kidney to prevent progression of chronic kidney disease, congestive heart failure, cardiovascular disease and overall mortality are well known.
Now, there is evidence that GLP-1 receptor agonists, currently used for weight loss and reducing blood glucose, are effective, too.
The first kidney or cardiorenal outcome trial with an SGLT2 inhibitor, CREDENCE, was done in patients with type 2 diabetes, mostly because canagliflozin (Invokana, Janssen) was already on the market for blood glucose lowering in type 2 diabetes and previous CV outcome trials had already shown evidence of maintaining kidney function, as predicted, in these patients with the purest form of metabolic kidney disease.
However, all kidney diseases have a metabolic component, even if it is secondary to an autoimmune, infectious, genetic or other cause, so other types of CKD were studied in the DAPA-CKD and EMPA-Kidney trials of dapagliflozin (Farxiga, AstraZeneca) and empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly), respectively. These trials also showed benefit in preventing the progression of CKD or major adverse renal events, but residual risks remained.
Cardiorenal effects of SGLT2 and incretin agents
SGLT2 inhibitors work directly on the kidney through the SGLT2 cotransporter to directly improve energy metabolism and function in the kidney. These work indirectly in the heart by improving cardiorenal hemodynamics and reducing fibrosis. These drugs do not address the underlying cause of metabolic dysfunction, which in our society is an unhealthy diet and lack of activity leading to obesity and, more specifically, the visceral insulin resistance-adiposity syndrome that is killing more people from cardiorenal disease than any infectious virus.
This syndrome indicates that there is too much fat in and around our organs, leading to increased chemokines, cytokines and hormones that promote systemic inflammation, insulin resistance, diabetes, hypertension, dyslipidemia, kidney dysfunction and fibrosis. This ultimately leads to cardiorenal dysfunction and death. BMI is not a good measure of visceral fat; waist circumference is better, but even that is not perfect. Each person probably has a visceral fat threshold that is genetically determined.
Incretin mimetics — GLP-1 receptor agonists and GLP-1/GIP receptor agonists — are the first class of drugs to address the underlying cause of metabolic syndrome by treating the visceral insulin resistance-adiposity syndrome that causes it. This is probably their main effect, but there are GLP-1 receptors throughout the body, including the kidney and heart, that are involved with improving the efficiency of nutrient storage. In the kidney, GLP-1 receptors on the renin-producing cells decrease renin production, leading to a decrease in angiotensin 2, proximal sodium transport, intraglomerular pressure and albuminuria. This improves energy metabolism in the kidney and reduces nutrient loss in the urine.
These drugs also improve nutrient storage by augmenting insulin synthesis and secretion, which is glucose dependent, and decreasing glucagon production, appetite and gastrointestinal (GI) motility. These drugs also improve endothelial function both directly and indirectly, possibly by reducing inflammation and endothelin. Their main adverse effect is GI, mainly nausea and vomiting, which can occasionally lead to dehydration. These drugs do not cause diabetic ketoacidosis, like occasionally SGLT2 inhibitors can, because these medications increase insulin levels while reducing body fat.
The initial incretin mimetics were exendin-based GLP-1s, which were expected to be better glucose-lowering drugs — that promoted weight loss — than dipeptidyl peptidase IV inhibitors. The development of more potent and longer-acting synthetic analog incretin mimetics, particularly semaglutide (Ozempic/Wegovy, Novo Nordisk) and tirzepatide (Mounjaro/Zepbound, Eli Lilly), not only produced greater blood glucose reduction, but also greater weight loss in most people. This of course led to a reduction in visceral fat and improved CV outcomes among patients with and those without type 2 diabetes and with a BMI of 27 kg/m2 or greater.
Primary kidney outcomes trial
The FLOW trial of 3,533 patients is the first primary kidney trial with an incretin mimetic, semaglutide. Like CREDENCE, FLOW was conducted in adults with type 2 diabetes. Participants were at high risk for progression with estimated glomerular filtration rate of 25 mL/min/1.73 m2 to 75 mL/min/1.73 m2 and albumin-to-creatinine ratio (ACR) from 100 mg/g to 5,000 mg/g. They were on maximally tolerated renin-angiotensin system inhibitors.
Drug discontinuation was slightly higher for semaglutide (12.6%) than placebo (11.3%), mostly driven by GI adverse events. Overall adherence to the trial regimen was good. The trial was stopped when the number of events needed for significant statistical analysis had occurred (741 total events). Mean follow-up was 3.4 years, longer than in the SGLT2 inhibitor trials.
The primary outcome of major adverse renal events had a relative risk ratio of 24% with a P value of .0003. Adjusted RR was 1.7 per 100 patient-years. There was a significant difference in eGFR of 0.94 mL/min/1.73 m2 from week 12 on in the chronic slope favoring semaglutide. Mean change in eGFR by the cystatin C equation from baseline to week 104 was 3.39 mL/min/1.73 m2 favoring semaglutide. There was an 18% lower risk for major adverse CV events, a 29% lower risk for CV death and a 20% lower risk for death from any cause in the semaglutide group compared with placebo. Semaglutide had a greater drop in ACR of 38% compared with placebo. The semaglutide group, on average, lost 4.1 kg more body weight and had a mean reduction in HbA1c of 0.81 percentage points greater than placebo.
Serious adverse events were reported in a lower percentage of participants in the semaglutide group than in the placebo group (49.6% vs. 53.8%). The most common were GI. There were fewer major adverse limb events in the semaglutide group.
Remaining questions
As mechanistically predicated and suggested by the CV outcomes trial, FLOW demonstrates that a drug that causes reduction in body weight and visceral fat — one of the main risk factors for type 2 diabetes and the development of cardiorenal disease — can reduce the progression of cardiorenal disease and mortality in patients with an eGFR of at least 25 mL/min/1.73 m2. FLOW, however, was not specifically designed to look at this association. As previously mentioned, BMI does correlate grossly with visceral fat but is not sensitive or specific for it. Certainly, comparing the primary outcome to people with BMI above and below 35 kg/m2 does not rule out an association with visceral fat. Incretin agonists that cause greater reductions in weight and HbA1c seem to also have greater cardiorenal benefits.
There are still some concerns with the use of semaglutide in patients with type 2 diabetes and CKD. No. 1, not everyone can tolerate these agents due to the GI effects. No. 2, the cost is prohibitive for some. No. 3, and most importantly, we do not know if people with BMI less than 25 kg/m2 or with significant sarcopenia can safely benefit from taking these drugs due to weight loss and loss of muscle mass. It would also be nice to know if higher doses of semaglutide ( 2 mg) would provide greater benefit safely.
Other questions that need to be answered are whether semaglutide provides similar benefit in patients with CKD without diabetes. The SELECT trial seems to suggest that it does. The SELECT trial, unfortunately, did not measure cystatin C-based eGFR to distinguish eGFR changes due to muscle mass, and it was not a CKD trial. Finally, we need to determine whether there is a benefit of combination therapy with SGLT2 inhibitors and nonsteroidal mineralocorticoid receptor antagonists. A recent meta-analysis suggests a significant cardiorenal disease event-free survival benefit.
Some of these questions may be partially answered with stronger incretin agonists, such as tirzepatide and retatrutide (Eli Lilly). Cardiorenal studies are being done with these drugs. The key will be to reduce visceral fat while maintaining muscle mass.
There are also exciting CKD studies being done with newer classes of medications, such as aldosterone synthase inhibitors, an interleukin-6 antagonist (ziltivekimab, Novo Nordisk) and endothelin receptor antagonists.
An important thing to consider from the FLOW trial is that if we treat patients with type 2 diabetes early on, before they have CKD or even before they have diabetes, when they just have obesity, can we prevent the development of the visceral insulin resistance-adiposity syndrome and metabolic cardiorenal disease? Diabetes prevention or delay has been seen with tirzepatide. The future looks bright for significantly reducing metabolic cardiorenal disease.
- References:
- EMPA-KIDNEY Collaborative Group. N Engl J Med. 2023;doi:10.1056/NEJMoa2204233.
- Heerspink HJL, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2024816.
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- Sloan LA. J Diabetes. 2019;doi: 10.1111/1753-0407.12969.
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- For more information:
- Lance Sloan, MD, MSE, FACE, FASN, FACP, FEAA, FASPC, is medical director of the Texas Institute for Kidney and Endocrine Disorders. He can be reached at tikedlufkin@gmail.com.
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