ACC: Cardiologists can use novel therapies to lower CV risk in type 2 diabetes
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Cardiologists can use SGLT2 inhibitors and GLP-1 receptor agonists to help reduce risk for major adverse CV events in patients with type 2 diabetes, according to an expert consensus decision pathway from the American College of Cardiology.
This document, which was published in the Journal of the American College of Cardiology, is an update to the 2018 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients with Type 2 Diabetes and Atherosclerotic Cardiovascular Disease.
“There’s been evolution in the care that we can provide patients with type 2 diabetes and cardiovascular disease because of the number of new therapies that have evidence of cardiovascular benefit,” Brendan M. Everett, MD, MPH, FACC, associate professor of medicine at Brigham and Woman’s Hospital and Harvard Medical School and co-chair of the writing committee, told Healio. “These therapies were initially developed to treat blood glucose in patients with diabetes and now have been shown to have important cardiovascular benefits. Many of them have been convincingly shown to reduce the risk of heart attack, stroke, hospitalization for heart failure and cardiovascular death.”
SGLT2 inhibitors
Several randomized controlled trials in patients with type 2 diabetes have shown that SGLT2 inhibitors reduced major adverse CV events, particularly in those with established ASCVD and/or diabetic kidney disease. This class of drugs also reduced risk for HF hospitalization.
Inhibiting SGLT2 leads to glucose lowering, in addition to weight loss, diuretic and natriuretic effects and systolic BP lowering. Changes in traditional risk factors including lipids and HbA1c do not seem to be the key reasons behind the benefits of SGLT2 inhibitors on CV and renal outcomes, according to the authors.
“There are now absolutely compelling data for the medications discussed here to improve ‘hard’ cardiovascular and renal outcomes in patients with diabetes. Their effects on blood glucose are, frankly, less important than their CV and renal benefits. We as cardiologists need to get comfortable prescribing these drugs in order to achieve the best possible outcomes for our patients,” Sandeep R. Das, MD, MPH, FACC, associate professor of internal medicine at the University of Texas Southwestern Medical Center and co-chair of the writing committee, said in an interview.
Findings from trials that showed CV benefits with SGLT2 inhibitors have led to FDA approvals. Empagliflozin (Jardiance, Boehringer Ingelheim) was approved to reduce risk for CV death in patients with type 2 diabetes and established CVD. Canagliflozin (Invokana, Janssen) was also approved to reduce risk for major adverse CV events in patients with established CVD, reduce the risk for diabetic nephropathy progression and prevent HF hospitalizations in patients with diabetic kidney disease and albuminuria. A 10-mg dose of dapagliflozin (Farxiga, AstraZeneca) was approved to reduce risk for HF in patients with type 2 diabetes who have established ASCVD or at high risk for developing the disease. This drug was also approved to treat HF in patients regardless of diabetes status.
Dapagliflozin, canagliflozin and empagliflozin have shown favorable effects on kidney function in patients with type 2 diabetes, the authors wrote.
“Mechanisms to explain these observations may include tubuloglomerular feedback, reduction in glomerular hypertension, containment of hyperfiltration injury and effects on sodium-hydrogen exchange,” Das and colleagues wrote.
Despite its benefits, there are some safety concerns with SGLT2 inhibitors such as risk for genital mycotic infections.
“Although these infections are usually not serious and tend to resolve with a brief course of antifungal agents, careful education and monitoring should take place in patients considered to be at high risk of infectious complications including the immunocompromised,” Das and colleagues wrote.
Other concerns with SGLT2 inhibitors include diabetes ketoacidosis, lower limb amputation and increased risk for hypotension and volume depletion. Patients should have their amputation risk monitored with regular foot exams, the authors wrote.
GLP-1 receptor agonists
GLP-1 receptor agonists have also shown benefits for CV event prevention in patients with type 2 diabetes, especially in those with established ASCVD. Dulaglutide (Trulicity, Eli Lilly & Co.), albiglutide (Tanzeum, GlaxoSmithKline; not available for commercial use in the U.S.), injectable semaglutide (Ozempic, Novo Nordisk) and liraglutide (Victoza, Novo Nordisk) have conferred reductions in major adverse CV events. GLP-1 receptor agonists reduce glucose and have beneficial effects on determinants of CV risk including BP, weight, inflammation and triglycerides, the authors wrote.
Most CV outcomes trials that assessed GLP-1 receptor agonists used a major adverse CV outcome of nonfatal MI, CV death or nonfatal stroke. A meta-analysis found that this benefit may be restricted to those with established ASCVD, with no benefit in patients with CV risk factors without ASCVD. In contrast, the REWIND trial found that dulaglutide had similar benefits for primary and secondary prevention. Dulaglutide is the only GLP-1 receptor agonist approved by the FDA for CVD risk reduction in patients with and without ASCVD.
Some studies suggest that some GLP-1 receptor agonists may offer modest renal benefits, although this has to be confirmed in a randomized trial that has a primary renal outcome.
Safety concerns associated with GLP-1 receptor agonists include nausea and vomiting, which are often transient with longer-acting GLP-1 receptor agonists and can be mitigated by escalating the dose. Patients may also be educated in how to reduce their meal size. Other concerns with this drug class include an increased risk for gallbladder disease, modest elevations in heart rate, increased risk for hypoglycemia and diabetic retinopathy complications, the authors wrote.
A patient-clinician discussion is recommended when considering if an SGLT2 inhibitor or a GLP-1 receptor agonist may benefit, especially for those with type 2 diabetes with or at very high risk for ASCVD, diabetic kidney disease and/or HF. SGLT2 inhibitors are recommended for patients with type 2 diabetes and HF, particularly HF with reduced ejection fraction, at high risk for developing HF, clinically evident ASCVD, diabetic kidney disease or any combination of these conditions. GLP-1 receptor agonists are recommended for patients with established or at very high risk for ASCVD. Patients may not be eligible for either class of drug if they are subsequently hospitalized or diagnosed with HF, ASCVD and/or diabetic kidney disease.
“The most important takeaway is that cardiologists should think about these two classes of medications, SGLT2 inhibitors and GLP-1 receptor agonists, as being important tools for them to use to help improve the outcomes of their patients with cardiovascular disease and diabetes,” Everett said in an interview. “Typically, the cardiologists are treating their patients’ cardiovascular disease, rather than their diabetes. So, for the cardiologist, these drugs should be seen as new tools to help them improve their patients’ cardiovascular outcomes.”
The authors wrote that SGLT2 inhibitors for CV benefit should start at the lowest dose tested in CV and renal outcomes trials such as 10 mg for dapagliflozin, 100 mg for canagliflozin and 10 mg for empagliflozin, while GLP-1 receptor agonists should be initiated at the lowest dose then uptitrated in a stepwise fashion to doses used in trials or a maximally tolerated dose.
“We hope that cardiologists will use the document as a tool to help them understand the benefits, the risks and then how to utilize the medications. We hope the document will help cardiologists decide which medication might be best used in the patient sitting in front of them,” Everett told Healio. “There’s a lot of important variability patient to patient both in terms of their disease process and in terms of the patient’s own preferences, values and goals, so we hoped to offer guidance to cardiologists as to which medication to use and then how to use it, how to prescribe it, and what to watch for in terms of benefits and risks so they can begin to be comfortable with two classes of medications they generally wouldn’t have considered using in the past.”
For more information:
Sandeep R. Das, MD, MPH, FACC, can be reached at sandeep.das@utsouthwestern.edu.
Brendan M. Everett, MD, MPH, FACC, can be reached at beverett@partners.org.
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