Review Urges Wider Use of Cardioprotective Glucose-Lowering Medications in T2D

By Brenda L. Mooney, /alert Contributor
Save to PDF By

More awareness of cardioprotective glucose-lowering medications is needed to help prevent microvascular and macrovascular complications in patients with type 2 diabetes,  according to a new review in Cardiovascular Endocrinology & Metabolism.

“Optimal glycemic control is well known to reduce the microvascular complications of retinopathy, nephropathy, and neuropathy. However, despite having multiple classes of antidiabetes medications, we have not been able to favorably affect the cardiovascular (CV) complications of diabetes, which cause considerable morbidity and premature CV mortality in patients with diabetes,”Sundre Mudaliar, MD, of the University of California San Diego School of Medicine and the San Diego Veterans Affairs Medical Center, explained. “The recent publication of the EMPA-REG Outcome and the LEADER studies demonstrating favorable CV outcomes with empagliflozin and liraglutide have led to a decision by the Food and Drug Administration to approve an additional indication (besides glucose lowering) - to reduce the risk of myocardial infarction, stroke, and CV death with liraglutide, and to reduce the risk of CV death with empagliflozin in adult patients with type 2 diabetes mellitus and established CV disease. This represents a paradigm shift in diabetes management and will have a major impact on diabetes treatment algorithms.”


Diabetes medication. Source: Getty

Noting that it has been nearly 100 years since the discovery of insulin for treatment of diabetes, Mudaliar recounts how, 20 years ago, UK Prospective Diabetes Study documented the benefits of intensive glucose control on microvascular complications in patients with type 2 diabetes mellitus. Despite the availability of a dozen classes of agents to treat diabetes, he adds, until recently,  no diabetes medication has shown proven benefits on cardiovascular disease (CVD), which is a major cause of morbidity and mortality in T2DM. 

In fact, according to the article, some therapies might have gone the other way. It describes how some medications such as the glitazones and saxagliptin (a DPP-4 inhibitor) actually appear to  increase the risk of hospitalization for heart failure and how, as shown in the Action to Control Cardiovascular Risk in Diabetes study, tight glycemic control increased cardiovascular and all-cause mortality.

“The recent publication of the EMPA-REG OUTCOME study in 2015 documenting a significant reduction in CV and all-cause mortality, and hospitalization for HF with an SGLT2 inhibitor (empagliflozin) truly represents a landmark in the field of diabetes treatment,” Mudaliar wrote. “This was followed in 2016 by the LEADER study, which reported a significant reduction in CV mortality with a GLP-1 agonist (liraglutide). Subsequently, in 2017, the CANVAS and the SUSTAIN-6 studies showed potential CV benefits with canagliflozin (an SGLT2 inhibitor) and semaglutide (a GLP-1 agonist) Recently, the FDA approved new indications for empagliflozin to reduce the risk of CV death and for liraglutide to reduce the risk of major adverse CV events and CV death in adult patients with T2DM and established CV disease.”

The review emphasized that glycemic control itself does not reduce the excess CV morbidity/mortality that affects most T2DM patients but said it is encouraging that liraglutide and empagliflozin, have shown CV benefits in large randomized trials. The Food and Drug Administration granted additional indications to reduce the risk of myocardial infarction, stroke, and CV death with liraglutide, and to reduce the risk of CV death with empagliflozin in adult patients with T2DM and established CV disease. 

Mudaliar made a strong recommendation on how to use those drugs .”In these patients, if there are no contraindications, and on the basis of individual considerations and cost issues, liraglutide and empagliflozin should be the drugs of choice for step-up treatment after metformin failure and perhaps even as initial combination therapy with metformin or as monotherapy in treatment-naive patients,” he wrote. “In selected patients, on the basis of the risk/benefit ratio, one may also consider combining both liraglutide and empagliflozin (with or without metformin) as an off-label indication. This combination would combine the potential antiatherosclerotic effects of liraglutide (reduction of MI/stroke/CV death) with the potential hemodynamic/myocardial metabolic benefits of empagliflozin (reduction of hospitalization for CHF and CV death).”

He suggested the situation could be different in T2D patients with advanced heart failure or chronic kidney disease, adding, “the studies are ongoing and in these patients, the risks/benefits will need to be determined on an individual basis.” 

The review also pointed out that it is not currently clear whether the CV benefits observed with liraglutide and empagliflozin are class effects of GLP-1 agonists/SGLT2-inhibitors or compound-specific effects.