AHA: SGLT2 inhibitors, GLP-1 receptor agonists offer cardiorenal protection
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Trials of SGLT2 inhibitors and GLP-1 receptor agonists, typically treatments for type 2 diabetes, have demonstrated potential CV and kidney benefits , according to a scientific statement from the American Heart Association.
Published in Circulation, the statement outlines specific CV and chronic kidney disease effects of SGLT2 inhibitors and GLP-1 receptor agonists in the treatment of diabetes. The writing group discussed their potential incorporation into a multidisciplinary approach to diabetes care.
“There has been an explosion of high-quality data in the cardio-renal-metabolic space with significant heart and kidney benefits afforded by two newer antihyperglycemic agents: the SGLT2 inhibitors and the GLP-1 receptor agonists,” Janani Rangaswami, MD, FACP, FAHA, associate chair of research in the department of medicine at Einstein Medical Center, associate clinical professor at the Sidney Kimmel College of Thomas Jefferson University in Philadelphia and chair of the statement writing committee, told Healio. “These data are practice-changing in both cardiology as well as nephrology and usher in a new era of disease-modifying therapies in heart and kidney disease. Thus, a scientific statement on the cardiorenal benefits with these agents in patients with kidney disease is timely and important to summarize current evidence and provide guidance to the cardiology/nephrology community on how to incorporate these agents in the decision-making pathways for the care of these patients in a multidisciplinary fashion.”
CV protection
Improvements in BP and volume control associated with the diuretic effects of SGLT2 inhibitors may play a role in the HF-specific benefits of the treatment, according to the scientific statement. The DAPA-HF trial reported a modest reduction in diuretic use with SGLT2 inhibitor dapagliflozin (Farxiga, AstraZeneca) added to standard diuretic therapy in HF with reduced ejection fraction.
Healio previously reported on the primary results of DAPA-HF from the 2019 European Society of Cardiology Congress, which demonstrated that among patients with HF, with and without diabetes, the SGLT2 inhibition with dapagliflozin reduced the risk for worsening HF and CV mortality when added to standard diuretic therapy.
Another randomized trial (Hallow KM, et al. Diabetes Obes Metab. 2018;doi:10.1111/dom.13126) demonstrated that osmotic diuresis with dapagliflozin produced a twofold greater reduction in interstitial volume compared with blood volume. According to the statement, SGLT2 inhibition may selectively reduce interstitial volume without simultaneous lowering of blood volume.
“SGLT2 inhibition is a particularly appealing molecular approach to treat type 2 diabetes and chronic kidney disease,” the committee wrote. “SGLT2 expression increases in the setting of type 1 or type 2 diabetes. SGLT2 inhibition increases the delivery of sodium, along with glucose and chloride (accompanying sodium), to the macula densa, where increased solute uptake activates the tubuloglomerular feedback pathway to promote afferent arteriole vasoconstriction, with a resultant decrease in intraglomerular pressure.”
In the pancreas, SGLT2 inhibition confers increased glucagon, which may contribute to a higher availability of ketones, the committee wrote. It is uncertain whether increased ketones in turn confers preferential use by cardiomyocytes or key cell types in the kidney over fatty acids.
The LEADER trial, which assessed CV outcomes in patients with diabetes treated with the GLP-1 receptor agonist liraglutide (Victoza, Novo Nordisk) compared with placebo, found that incidence of CV death, nonfatal MI or nonfatal stroke was lower among patients in the liraglutide group (HR = 0.87; 95% CI, 0.78-0.97). Moreover, patients with diabetes and chronic kidney disease appeared to derive greater benefit from treatment with liraglutide (HR = 0.69; 95% CI, 0.57-0.85) compared with patients with better kidney function (HR = 0.94; 95% CI, 0.83-1.07).
Moreover, findings from the SUSTAIN-6 trial, which evaluated long-term CV outcomes among patients treated with the GLP-1 receptor agonist semaglutide (Ozempic, Novo Nordisk), showed a reduction in the composite outcome of CV death, nonfatal MI or nonfatal stroke (HR = 0.74; 95% CI, 0.58-0.95) compared with placebo.
“The PIONEER-6 trial demonstrated noninferiority with the oral formulation of semaglutide with respect to the primary composite outcome for major adverse cardiovascular events, as well as risk reductions for individual components,” the committee wrote. “Oral semaglutide is undergoing further specific cardiovascular outcome testing in the SOUL trial.”
According to the statement, analysis of the LEADER trial found significant reduction in a composite of new-onset persistent macroalbuminuria, persistent doubling of serum creatinine, end-stage kidney disease or death resulting from kidney disease among patients who received liraglutide (HR = 0.78; 95% CI, 0.67-0.92).
“More recent data from the DAPA-CKD trial as well as the EMPEROR-Reduced trial show benefits in chronic kidney disease and HF even in patients without diabetes,” Rangaswami said in an interview.
Healio previously reported on the results of the DAPA-CKD trial presented at the European Association for the Study of Diabetes and the ESC Congress as well as the findings of EMPEROR-Reduced presented at the ESC Congress.
‘Standard of care’
“The SGLT2 inhibitors are now part of standard of care in patients with HFrEF and also have secondary protective kidney benefits in this population while the GLP-1 receptor agonists may afford more protection in patients with atherosclerotic CVD,” Rangaswami told Healio. “The cardiorenal benefits with both these drug classes are also seen in patients with preexisting chronic kidney disease. The SGLT2 inhibitors also have shown reduction in HF-related adverse outcomes and kidney function decline in nondiabetic patients.”
According to a press release from the AHA, the committee recommended the following approach to treating patients who may benefit from SGLT2 inhibitors and GLP-1 agonists:
- Identify patients early and in an ongoing manner who may benefit from the protective and preventive effects of these medicines.
- Tailor medication choices to each individual patient.
- Monitor and control high BP.
- Identify risks for hypoglycemia and educate patients on the signs so they may seek treatment.
- Adjust all medications in tandem with SGLT2 inhibitors and GLP-1 receptor agonists and consider the burden of polypharmacy, which is common among patients with diabetes.
- Counsel patients on the risks and symptoms of euglycemic diabetic ketoacidosis when taking SGLT2 inhibitors, which is serious and can be fatal.
- Regularly screen and counsel patients on regular foot care to prevent ulcers or blisters that may become infected and lead to amputation.
“We still need to understand the role for combination therapy with both these drug classes, what circumstances and who would benefit,” Rangaswami said in an interview. “We need a better understanding of any individual drug-specific characteristics that may show differences in cardiovascular outcomes within a given drug class. Finally, we need a strong understanding of the existing barriers to implementing the use of these drugs in high-risk patients in real-world practice to see the results from trials translated into clinical practice.”
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