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ACC: SGLT2 inhibitors, GLP-1 agonists reduce CV risk in type 2 diabetes
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Recent studies have shown that sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists significantly improve CV outcomes, according to an American College of Cardiology expert consensus decision pathway published in the Journal of the American College of Cardiology.
The agents are prescribed to lower glucose in patients with type 2 diabetes and atherosclerotic CVD.
“Ultimately, the main goals of care for these high-risk patients should be improving survival and quality of life,” Sandeep R. Das, MD, MPH, FACC, associate professor in the division of cardiology at UT Southwestern Medical Center in Dallas and co-chair of the writing committee, and colleagues wrote. “Achieving these important goals requires a team-based approach to achieve optimal outcomes. If used appropriately, the SGLT2 inhibitors and GLP-1 [receptor agonists] discussed in this document should significantly reduce CV morbidity and mortality in these patients.”
CV outcomes trials
Results from EMPA-REG Outcome and CANVAS found that the risks for major adverse CV events and HF hospitalization were reduced with the sodium-glucose cotransporter 2 (SGLT2) inhibitors empagliflozin (Jardiance, Boehringer Ingelheim) and canagliflozin (Invokana, Janssen), respectively. SGLT2 inhibitors can also have positive effects on kidney function.
SGLT2 inhibition aids in lowering glucose by including glucosuria, according to the expert consensus decision pathway. CV benefits associated with this therapy may be a result of their natriuretic and diuretic effects, in addition to BP lowering and weight loss.
Some safety concerns are associated with SGLT2 inhibitors, such as intravascular volume contraction, increased risk for hypoglycemia with insulin, increased incidence of bone fractures and euglycemic ketoacidosis.
Glucagon-like peptide-1 (GLP-1) receptor agonists, specifically liraglutide (Victoza, Novo Nordisk), have also been shown to reduce CV risk in patients with type 2 diabetes. Studies have assessed the effects of other GLP-1 receptor agonists, including semaglutide (Ozempic, Novo Nordisk) and exenatide (Bydureon, AstraZeneca). Although they reduced the risk for major adverse CV events in these patients, the trials were either powered as a noninferiority trial or did not reach statistical significance. Lixisenatide (Adlyxin, Sanofi Aventis) is one GLP-1 receptor agonist that did not reduce the risk for atherosclerotic CVD in patients after ACS.
“Taken together, these results suggest the potential for clinically relevant heterogeneity within the class, although some of the differences between compounds may also be due to the doses tested or specific drug characteristics, or due to variations between patient populations and trial designs,” Das and colleagues wrote.
GLP-1 receptor agonists reduce glucose by increasing insulin secretion and decreasing glucagon secretion. This therapy may also have renal benefits, although an independent randomized trial has yet to confirm this, according to the expert consensus decision pathway. The exact mechanism of this therapy and its effect on CV risk has yet to be explained, although it may be connected with systolic BP lowering, LDL reductions and weight loss.
The most common adverse effects of GLP-1 receptor agonists are vomiting and nausea, and it may affect the absorption of oral medications taken with these therapies. Other concerns with the class include heart rate elevations and use in patients with prior gastric surgery.
Risk discussion needed
A discussion between a clinician and a patient regarding options and risk should be done before these therapies are initiated, especially during follow-up visits for patients with type 2 diabetes and atherosclerotic CVD, according to the expert consensus decision pathway. Patients who were subsequently hospitalized or diagnosed with HF or atherosclerotic CVD may be eligible for either of these therapies.
Selecting an SGLT2 inhibitor or a GLP-1 receptor agonist should be made based on what is most appropriate for the patient, which can be guided by medical history and patient preferences. Although more data are needed to determine which treatment is suitable for which patient, patients who are at high risk for HF may benefit more from an SGLT2 inhibitor. GLP-1 receptor agonists may be better suited for patients with severe peripheral artery disease, osteoporosis, peripheral neuropathy, prior amputation or active lower-extremity soft-tissue ulcers or infections.
Whether a patient is treated with metformin before initiating an SGLT2 inhibitor or GLP-1 receptor agonist may not be relevant, as there are limited data suggesting no heterogeneity in CV benefits.
Trials have not assessed the CV benefits of combining both therapies in patients with atherosclerotic CVD.
“Mechanistically, these drug classes have opposite effects on glucagon, suggesting the possibility of an interaction, and the out-of-pocket cost of using drugs from both classes together would likely be very high,” Das and colleagues wrote.
Results from the DURATION-8 trial found that there were greater BP and body weight reductions in patients who were treated with exenatide and dapagliflozin (Farxiga, AstraZeneca). It may be reasonable to use an SGLT2 inhibitor and a GLP-1 receptor agonist if it is clinically indicated, according to the expert consensus decision pathway.
While a patient is treated with either therapy, clinicians should monitor patients for any sign of safety concerns, including genital mycotic infections, euglycemic diabetic ketoacidosis, insulin dose and estimated glomerular filtration rate.
Conversations between clinicians and patients should continue after the therapy is initiated to potentially improve utilization and adherence.
“This area of care for affected patients is likely to continue evolving rapidly,” Das and colleagues wrote. “We anticipate that the algorithms proposed here will change as new evidence emerges, but that the overarching goal of improving CV outcomes in patients with [type 2 diabetes] and clinical [atherosclerotic] CVD will remain consistent.”
“The ACC Expert Consensus Decision Pathway, along with the [American Diabetes Association] and [European Association for the Study of Diabetes], all now recommend a comprehensive cardiovascular program for adults with type 2 diabetes and established cardiovascular disease that includes a treatment such as Jardiance, shown to improve cardiovascular outcomes in this population,” Thomas Seck, MD, senior vice president of medicine and regulatory affairs for Boehringer Ingelheim, said in a press release. “These recommendations reflect a fundamental change in the management of diabetes, moving beyond glucose control to a broader strategy of comprehensive cardiovascular risk reduction.” – by Darlene Dobkowski
Disclosures: Das reports no relevant financial disclosures. Seck is an employee of Boehringer Ingelheim. Please see the expert consensus decision pathway for all other authors’ relevant financial disclosures.
Perspective
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Darren K. McGuire, MD, MHSc
Two SGLT2 inhibitors and two GLP1 receptor agonists have proven CV benefit: empagliflozin, canagliflozin, liraglutide and semaglutide. The benefits appear independent of the glycometabolic effects of the medications. For patients with type 2 diabetes and clinical ASCVD, these drugs should be considered for CV risk reduction independent of glucose management considerations, including prescription by cardiologists.
This pathway has implications for clinical practice. As per the design and focused intent, these expert clinical decision pathways have direct clinical relevance from beginning to end. The document is a concise, outstanding summary review of the data with clear recommendations on how to apply in the clinical setting.
Moving forward, we need to evaluate whether such CV benefits may apply to type 2 diabetes patients with increased risk for ASCVD but not yet with ASCVD. The small subsets without ASCVD in most trials to date have not demonstrated any suggestion of benefit, but perhaps the trials were too short to detect in a lower risk cohort. More recently, data from DECLARE TIMI 58 trial (Wiviott SD, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1812389) that came out after this consensus document was completed revealed that the SGLT2 inhibitor dapagliflozin indeed has benefits on risk for CV death/hospitalization for HF that applies to patients with ASCVD and similarly to those with ASCVD risk factors.
We also need to evaluate if the benefits of SGLT2 inhibitors and GLP1 receptor agonists are complementary/additive, ie, whether these should be used together. Each class is approved to be used with the other for glucose-lowering effects, but whether there is incremental CV risk reduction with the combination remains unclear.
The data are consistent and robust, now at a level supporting 1A indication for use for CV risk reduction. Cardiologists will have to become comfortable prescribing these medications and incorporating their use into routine clinical practice — not for the purpose of managing blood glucose, but specifically for their CV benefits.
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