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SGLT2 inhibitors may have great potential in reducing HF in diabetes
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SAN ANTONIO — Several studies on SGLT2 inhibitors have shown that they may be able to reduce HF in patients with diabetes, according to a presentation at the American Society for Preventive Cardiology Congress on CVD Prevention.
SGLT2 inhibitors may have the potential to be antiarrhythmic drugs, as they may be able to shorten QTs and decrease QT/T wave dispersion, Robert J. Chilton, DO, FACC, FAHA, professor of medicine/cardiology, associate program director of interventional cardiology and director of the catheterization lab at the University of Texas Health Science Center in San Antonio, said during the presentation. Data, particularly the EMPA-REG OUTCOME trial, showed that these medications can also reduce CV death.
Other potential benefits
The benefits of SGLT2 inhibitors may be related to improved microcirculation not only in the heart, but potentially all over the body.
“If you can affect the microcirculation to protect the heart especially, that tells you where things are really starting from,” Chilton said. “We didn’t start having heart disease; we started with insulin resistance.”
Other benefits seen in patients taking SGLT2 inhibitors included reduced inflammation and improved microcirculation, proinflammatory markers with a new finding of potassium channel blockade.
Multiple risk factors are involved in HF in these trials in patients with diabetes, Chilton added. Similarly, he said, there has been a low prevalence of diabetes studied in HF trials.
“We’re going to have to wait, although there’s an increased number of new trials that will look at this in time,” Chilton said.
A patient’s risk for CVD is related to genetics, potentially more than clinical risk factors, according to the presentation.Mom and dad are very important to the CV risk of offspring.
“Certainly you can damage yourself at breakfast, lunch and dinner, but at the same time, once you develop insulin resistance, you have a problem,” Chilton said. “I’m not sure you can reverse it completely.”
Cardiologists need to think of patients with diabetes beyond the heart and kidneys, but rather consider the entire body in terms of atherosclerosis, according to the presentation.
Chilton mentioned that by the time a patient has a stent put in, it may be too late because disease has spread throughout the body and it is very difficult to correct years of prior disease development.
Kidneys pose another concern to cardiologists, although drugs like SGLT2 inhibitors may help protect them. It appears to be one of the most important advancements in diabetes-kidney protection in the last 20 years.
There have been numerous randomized CV endpoint trials that showed benefits with SGLT2 inhibitors.
“If you use a statin in order to reduce cardiovascular events, which was first developed by endocrine physicians, SGLT2 inhibitors are not far from statins in CV protection for HF, and they do reduce CV death that is not seen with statins. So why aren’t you using the drug? It’s a cardiovascular drug that also lowers your glucose, and spinning it in the reverse direction, if you reduce glucose (biomarker), you reduce cardiovascular events, especially CV death with empagliflozin. To me as a cardiologist, it decreases cardiovascular events and it lowers glucose.”
There will be more trials on the treatment of HF, but not all of them will have patients with diabetes, Chilton said. He added that the water loss and calorie loss associated with SGLT2 inhibitors is impressive.
“For a weight-loss drug, it is only approved for diabetes, but loss of 400 calories a day on any diet is pretty impressive,” Chilton said. “[Researchers] have a lot of things to consider."
The biggest potential for SGLT2 inhibitors may be in HF in patients with diabetes, although no drugs are currently addressing HF with preserved ejection fraction and show benefit.
“You might be able to do that with this new cardiometabolic drug,” Chilton said.
The patients in both the EMPA-REG OUTCOME and DECLARE-TIMI 58 trials cannot be compared since they are two completely different populations. There was an estimated 4% event rate per year in EMPA-REG OUTCOME vs. an estimated 2% in DECLARE-TIMI 58, Chilton said. The EMPA-REG OUTCOME trial had approximately 95% of patients at very high risk for CVD but the DECLARE-TIMI 58 trial had fewer high-risk patients.
SGLT2 inhibitors may be the beginning of a new era of medications, Chilton said.
He added, “You have metabolic drugs now that actually can decrease glucose and at the same time they have sodium loss and you lose calories and they can even in animals decrease cardiac fibrosis. This is a different time. These are not the drugs that you used years ago for heart failure; they’re a new kind.” – by Darlene Dobkowski
Reference:
Chilton RJ. Session 2: Diabetes Mellitus. Presented at: American Society for Preventive Cardiology Congress on CVD Prevention; July 19-21, 2019; San Antonio.
Disclosure: Chilton reports he has financial relationships with AstraZeneca, Boehinger Ingelheim, Eli Lilly and Merck Sharp & Dohme.
Perspective
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George L. Bakris, MD
Chilton makes the point that obesity is the root cause of microvascular disease of which diabetes is a contributor and results from obesity in most people. Microvascular injury affects the kidney, vasculature, eye and other organs. It starts to occur when glucose levels are above the upper range of normal and prior to the diagnosis of diabetes, ie, metabolic syndrome.
For the first time, among the eight classes of diabetes drugs, there are now two classes that have shown definitive CV risk reduction in multiple trials: the SGLT2 inhibitors, and the GLP-1 agonists. The CV benefits of these classes can’t be explained by glucose reduction alone, and evidence supports the notion they work by multiple mechanisms not fully defined but focused on reduction of inflammation.
The SGLT2 inhibitors have universally shown improvement in HF and reduced incidence in HF. The DAPA-HF study using dapagliflozin (Farxiga, AstraZeneca) just reported that the primary outcome, which was HF prevention, was positive. Moreover, the SGLT2 inhibitors are the only class of glucose-lowering drugs to slow advanced kidney disease progression from diabetes.
Cardiologists clearly have a role in reducing the incidence of HF and now for the first time with agents that lower glucose and not just BP and lipid management. Thus, in people with diabetes regardless of glucose control down to an estimated glomerular filtration rate (eGFR) of 30 mL/min/1.73 m2, these agents should be part of the armamentarium for CV risk reduction. While they do not lower glucose at levels below an eGFR of 45 mL/min/1.73 m2, they have been shown to reduce HF risk substantially in five randomized trials as well as reduce mortality risk. Moreover, as I have said in a recent publication (Bakris GL, et al. Am J Kidney Dis. 2019;doi:10.1053;j.ajkd.2019.05.009.), “SGLT2 inhibitors are cardiorenal risk-reducing agents that have glucose lowering as a beneficial side effect.”
SGLT2 inhibitors are clearly anti-inflammatory as evidenced by their effects on the inflammasome. They also block expression of angiotensinogen in the kidney of diabetic animals and reduce oxidant stress by more than 60%. They also increase ketones. All of these are potentially beneficial to the heart. However, definitive mechanism for both GLP-1 agonists and SGLT2 inhibitors resulting in these outcomes are unclear.
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