Glucose-Lowering Drugs to Reduce Cardiovascular Disease

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Posted by Carla Rothaus

What are some of the areas of uncertainty regarding the use of SGLT2 inhibitors and GLP-1 receptor agonists in patients with type 2 diabetes? 

The treatment of patients with diabetes and established cardiovascular disease (and in selected patients at high risk for a cardiovascular disease) should include a glucose-lowering medication with demonstrated cardiovascular benefit, including specific agents from the glucagon-like peptide-1 (GLP-1) receptor agonist or sodium–glucose cotransporter type 2 (SGLT2) inhibitor classes. Read the NEJM Clinical Practice article here.

Clinical Pearls

Q: What is known about the effects of insulin on cardiovascular outcomes in patients with type 2 diabetes?

A: Studies of the effects of insulin on cardiovascular outcomes have been inconsistent. No increased risk of myocardial infarction or diabetes-related death was observed among participants assigned to insulin therapy as compared with conventional treatment in the United Kingdom Prospective Diabetes Study (UKPDS) 33.

Q: How did the dipeptidylpeptidase-4 inhibitors compare with placebo in cardiovascular outcome trials?

A: Dipeptidylpeptidase-4 inhibitors were shown to be noninferior or safe as compared with placebo in cardiovascular outcome trials, with the exception of saxagliptin, which was associated with a significantly increased risk of hospitalization for heart failure.


Morning Report Questions

Q: Does metformin reduce the risk of cardiovascular disease?

A: Metformin is widely considered to be the drug of choice for most patients with type 2 diabetes. The findings in UKPDS 34 suggested cardiovascular benefits. Among 753 overweight participants with newly diagnosed type 2 diabetes assigned to receive intensive treatment with metformin or conventional treatment (mean glycated hemoglobin level, 7.4% and 8.0%, respectively), those randomly assigned to receive metformin had significant reductions in the risk of myocardial infarction (39%) and diabetes-related death (42%) during the 10-year trial period, and the benefits persisted during subsequent long-term observation. However, a meta-analysis that included the results of this trial and other, smaller trials concluded that owing to limited data, there was uncertainty as to whether metformin reduces the risk of cardiovascular disease.

Q: What are some of the areas of uncertainty regarding the use of SGLT2 inhibitors and GLP-1 receptor agonists in patients with type 2 diabetes?

A: Several mechanisms have been proposed for the cardiovascular effects of SGLT2 inhibitors and GLP-1 receptor agonists, and it remains uncertain whether the benefits are drug-specific or classwide. With some exceptions, more than two thirds of all participants in cardiovascular outcome trials had established atherosclerotic cardiovascular disease or heart failure. Various definitions have been used to classify the remaining participants at high risk for atherosclerotic cardiovascular disease. Subgroup analyses in some trials suggest similar cardiovascular effects in patients at high risk, but the evidence of benefit in this population is less definitive. Since patients with glycated hemoglobin targets of less than 6.5% or 7.0% and those with no or minimal cardiovascular risk factors were not enrolled in the cardiovascular outcome trials, it remains unclear whether the results can be generalized to these patients. Also, it is not known whether the combination of a GLP-1 receptor agonist and an SGLT2 inhibitor would confer more cardiovascular benefit than either alone.

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