December 05, 2021
3 min read
Kelesidis T. Drug development for cardiometabolic disorders — focusing on the patient. Presented at: World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease; Dec. 2-4, 2021; Los Angeles (hybrid meeting).
Keledisis reports no relevant financial disclosures.
Emerging data suggest immunotherapies and novel peptides that target gut inflammation could serve as complementary agents to available diabetes drugs to more effectively target cardiometabolic diseases, according to a speaker.
Atherosclerotic cardiovascular disease, obesity and metabolic syndrome have increased in prevalence worldwide, and understanding the pathogenesis of this cardiometabolic syndrome is essential for developing effective treatments, Theodoros Kelesidis, MD, PhD, associate professor of medicine at the University of California Los Angeles, said during a presentation at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. Increased systemic inflammation and oxidative stress drive the oxidation of lipids and the accumulation of triglycerides in metabolically active tissues, such as the liver and adipose tissue. This leads to the release of free fatty acids in the blood that, combined with other alterations like altered adipokines, collectively drive the development of insulin resistance, type 2 diabetes, atherosclerosis, coronary artery disease and nonalcoholic fatty liver disease, Kelesidis said.
“It is important to target these pathways, because existing diabetes drugs may not be able to fully control the cardiometabolic syndrome,” Kelesidis said.
Complementing existing agents
Large clinical trials have established the cardioprotective effects of GLP-1 receptor agonists and SGLT2 inhibitors for people with type 2 diabetes at high risk for CVD. These agents have also demonstrated favorable cardiometabolic effects for people without diabetes, Kelesidis said. GLP-1 receptor agonists, for example, have been shown to reduce body weight, blood pressure, atherosclerosis and inflammation; an ongoing study is anticipated to show GLP-1 receptor agonists also confer a heart failure benefit, he said. Likewise, SGLT2 inhibitors have shown promise as effective agents for treating chronic kidney disease.
“Each patient has different risk factors, so it is important we have treatments that can target those specific factors, independent of a glucose-lowering effect,” Kelesidis said. “This is important, because obesity, chronic kidney disease and HF are important parameters of cardiometabolic disease, with and without diabetes.”
Emerging evidence suggests combination therapy with GLP-1 receptor agonists and SGLT2 inhibitors may have an additive effect on HbA1c, body weight and systolic BP, without increasing risk for hypoglycemia for adults with type 2 diabetes.
Despite the availability of such options, there remains a need for new treatments to complement GLP-1 receptor agonists and SGLT2 inhibitors to better treat cardiometabolic disease.
“In order to do that, it is important to understand the complex, inter-organ crosstalk in cardiometabolic syndrome,” Kelesidis said. “The gut, the liver, the muscle, the adipose tissue, they interact. They secrete hormones. Collectively, they affect the blood vessels all over the body and contribute to cardiometabolic disease.”
Immunotherapy, gut peptides: promising new targets
Several immunotherapies that target inflammation — already established in the pathogenesis of cardiometabolic syndrome — are currently under development to address the complex “crosstalk” between organs.
In the CANTOS trial, researchers found targeting the interleukin-1 beta innate immunity pathway with the monoclonal antibody canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent CV events compared with placebo, independent of lipid-level lowering. Similarly, in the LoDoCo2 trial, researchers found that adding low-dose colchicine to optimal medical therapy reduced risk for CV events by 31% among patients with chronic coronary disease.
Kelesidis cautioned that not all anti-inflammatory agents are beneficial. Among patients with stable atherosclerosis, low-dose methotrexate did not reduce levels of interleukin-1beta, interleukin-6 or C-reactive protein and did not result in fewer CV events than placebo. Research continues into whether targeting a single inflammatory mediator vs. broader mechanisms of inflammation is more effective, Kelesidis said.
“This evidence shows us that targeting a single inflammatory mediator may not be as effective,” Kelesidis said. “We may have to target broader mechanisms of inflammation. On the other side, if we use broad spectrum anti-inflammatory treatments, this increases the risk for off-target effects. This is quite complex.”
Agents are currently in development that target cytokines and their receptors and chemokines and their receptors, in addition to resolvins (bioactive lipids with a favorable anti-inflammatory effect), immune checkpoint inhibitors, use of select metabolites and agents that modulate cholesterol metabolism.
The intestine is also a therapeutic target in cardiometabolic syndrome, Kelesidis said. Agents such as apolipoprotein A-I mimetic peptides have been shown in preclinical studies to have pleiotropic antioxidant, anti-inflammatory and antiatherogenic properties, while also proving safe for use in humans. Data published in Metabolism in September demonstrated apolipoprotein A-I mimetics favorably influence the proinflammatory effects of endotoxin, cyclooxygenase 2 and production of bioactive lipids that collectively drive gut and systemic inflammation in chronic treated HIV, suggesting the peptides may be a novel therapy to treat cardiometabolic syndrome.
“With this emerging insight, it is really important to have a collaborative effort between clinicians — primary care physicians, endocrinologists and cardiologists — to focus on the patient and come up with an individual, optimized treatment to treat cardiometabolic disease,” Kelesidis said.a