Is Cardiovascular Risk Improvement a Result of Reduced Hemoglobin A1c?

Trials tested the hypothesis that treating patients with intensive therapy to target normal glycated hemoglobin A1c levels would positively affect cardiovascular risk. 

In every observational study involving people living with diabetes, a lower Hemoglobin A1c (HbA1c) is associated with a lower risk of cardiovascular events. The question remains if there is a correlation between the reduction in hemoglobin A1c and improved cardiovascular risk. Medical professionals have a difficult time with this question because randomized control trials have different findings from observational studies. Studies that directly test this hypothesis, such as ACCORD, ADVANCE, and VADT trials, report no cardiovascular benefit seen with patients with lower HbA1c levels. These randomized control trials tested the hypothesis that treating patients with intensive therapy to target normal glycated hemoglobin levels or tightening glycemic control from moderate to fairly tight levels of HbA1c would positively affect cardiovascular risk. The researchers found that it did not have any cardiovascular benefits; a reduced HbA1c did not reduce the risk of mortality but did reduce diabetic nephropathy by an estimated 20%. 

Observational studies that show an association between lower HbA1c and lower cardiovascular risk did not consider stage bias. Some observational studies do not consider the duration of time the patient has had diabetes. In an interview with Dr. Deborah Wexler, an Associate Professor of Medicine at Harvard Medical School, she stated that people who have diabetes, but not for very long, find it easier to control their diabetes. They have better HbA1c levels and less established cardiovascular disease. On the other hand, patients with longer-duration diabetes have higher HbA1c and have had more time to accumulate cardiovascular complications. Unfortunately, the correlation between lower HbA1c and lower risk of cardiovascular disease will always be there. It is difficult to separate the two in any observational study because of stage bias. Randomized control studies that focus primarily on HbA1c reduction and cardiovascular risk can untangle the two because they take stage bias into account. 

What is vital for decreasing cardiovascular risk is managing cardiovascular risk factors such as hypertension, hyperlipidemia, smoking cessation, and weight management. Treating patients to intensive glycemic control and moderate glycemic control has no benefit on cardiovascular benefits. Sodium-glucose transport protein 2 (SGLT-2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists are diabetes medications that reduce cardiovascular disease risk. Both GLP-1 and SGLT2 have cardioprotective properties linked to decreased cardiovascular mortality and reduced heart failure hospitalization. Dr. Wexler states that in SGLT2 inhibitors, people feel pretty strongly that the benefits from that medication are independent of the glucose-lowering effects. With the GLP-1 receptor agonist, it is harder to separate its cardiovascular benefit from its glucose-lowering effects because it is potent in lowering blood glucose. Medical professionals believe that SGLT2 and GLP-1 possibly have some direct antiatherogenic benefits. 

The greatest risk of death for people living with type 2 diabetes is from cardiovascular complications. To help prevent or lower the risk of death from cardiovascular diseases, health care providers should help manage risk factors appropriately. Risk factors contributing to cardiovascular disease and death are hypertension, hyperlipidemia, smoking, and being overweight. For people living with type 2 diabetes with high cardiovascular risk or established cardiovascular risk, medication therapy should include medication that lowers blood glucose and has additional benefits. These medications that provide more than one benefit are the SGLT-2 inhibitors and GLP-1 receptor agonists associated with cardiac benefit, weight loss, and no hypoglycemia. Other diabetes medications do not have the same cardioprotective benefits as SGLT-2 inhibitors and GLP-1 receptor agonists, so increased patient therapy is not recommended. 

Practice Pearls: 

• Two recommended diabetes medications that can be used in patients with type 2 diabetes and established cardiovascular diseases are sodium-glucose transport protein 2 (SGLT-2) Inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonist. 
• The management of risk factors associated with cardiovascular diseases such as hypertension, hyperlipidemia, smoking cessation, and weight management is important in reducing patient’s risk. 
• In randomized control trials, there is no correlation between the reduction in hemoglobin A1c and cardiovascular risk. 

Wexler, Deborah. “Hemoglobin A1c Reduction and CV Risk Improvement: Correlation, Causation, and Clinical Recommendations.” Practiceupdate. 12 Aug. 2021 

Jerrine Fletcher, Fourth Year Doctor of Pharmacy Candidate, Florida A&M University College of Pharmacy and Pharmaceutical Sciences, Institute of Public Health