What is the Best Diabetes Medication? One that Can Protect Your Heart Health

With Deepashree Gupta, MD, and Matthew Freeby, MD

Which medicine should you be taking to control your diabetes? That's a question that needs to be answered after your doctor takes into account several important factors, such as your personal medical history, including your heart health and your risk of kidney disease. As your doctor has no doubt told you, just having type 2 diabetes (T2D) puts you at increased risk of having heart disease and so both conditions should be tackled simultaneously.

Thankfully, more medications have become available in the last few years that have the ability to control your blood sugar and reduce the risks associated with heart disease, says Deepashree Gupta, MD, assistant professor of endocrinology at the University of California at Los Angeles (UCLA) David Geffen School of Medicine and an endocrinologist at UCLA Health Westlake Village.

Taking 2 drugs may be necessary to manage your diabetes and promote heart health.Having type 2 diabetes increases your risk of heart disease so you may need two medications to protect your health. Photo: 123rf

Dr. Gupta spoke about "So Many New Medications: Are They Better Than the Old Ones?" at the 5th annual Healthy Living with Diabetes Conference sponsored by UCLA.1

Taking a Look Back at the Changes in Drug Treatment for Diabetes

First, she laid out the risks, in realistic terms. "Diabetes results in a two to four-fold increased risk of coronary heart disease and cardiovascular death,"2she says so it’s just as important to have well-managed blood glucose as is it to also lessen the risks of heart disease.

Next, she gave a succinct overview of the new drug classes—both the pros and cons. As you read, you may finally begin to understand why your doctor may be suggesting a medication switch for your diabetes.

In past years, the research trials had been focusing only on the effects that diabetes medication has on blood sugar, Dr. Gupta says. Until 2007, the Food and Drug Administration (FDA) required only that diabetes drugs demonstrated a sustained reduction in blood sugar levels with an acceptable safety profile in order to gain approval for patient use.

That all changed when the rosiglitazone (Avandia) was found during clinically testing to nearly double (43%) the risk of heart attack.3 "This medication was extremely restricted beginning in 2008," she says. "This was a watershed moment, especially for the newer diabetes medicines."

In response to this alarming finding, an FDA advisory committee required the addition of a boxed warning to Avandia about the increased heart attack risk; that was done, and any access to its use was then restricted in 2010. The FDA took the added step of requiring a risk evaluation and risk mitigation procedure before prescribing Avandia, to be sure the benefits outweighed the risks in patients, says Dr. Gupta.

Heart Disease Protection Takes Center Stage in Newer Diabetes Medications

From that point on, new medications have had to demonstrate safety by proving in clinical studies that there is no unacceptable increase in cardiovascular risk compared to existing medicines. Researchers and drug makers had to formulate drug trials that included consideration of key factors associated with cardiovascular disease (CVD): stroke, heart attack, death from cardiovascular disease, hospitalization for unstable angina, and need for urgent revascularization procedures,4 according to the FDA.

This FDA guidance has had a major impact on the development of new diabetes medicines,4 by influencing all clinical studies to consider heart risks when testing diabetes medications for improvement in glucose control. "There are now 40 cardiovascular outcome trials" of new diabetes medicines, Dr. Gupta says.

Most of the focus has centered on two classes of drugs, the sodium-glucose cotransporter-2 (SGLT2) inhibitors and the glucose-like peptide-1 (GLP-1) agonists.

Examples of SGLT-2 inhibitors are canagliflozin (Invokana), dapagliflozin (Farxiga) and empagliflozin (Jardiance). The medicines work by preventing the kidneys from reabsorbing glucose into the bloodstream. They achieve this by blocking proteins known as sodium glucose transport proteins.

The class of GLP-1 agonists includes dulaglutide (Trulicity), exenatide (Byetta) and liraglutide (Victoza).  These diabetes medications work by mimicking a hormone produced by the body (GLP-1), which helps the pancreas produce insulin.

Benefits of Adding a Second Medication to Your Diabetes Treatment Plan

The SGLT-2 inhibitors have been shown to decrease the risk of cardiovascular death and hospitalization for congestive heart failure,5,6 Dr. Gupta says.

Among the studies she cited was one on Jardiance, involving more than 7,000 patients who had both diabetes and established heart disease who were than followed for about three years.5  The researchers reported an almost 14% reduction in the primary outcome studied—a composite of death from cardiovascular causes, nonfatal heart attack or nonfatal stroke.

"The cardiovascular improvement is probably occurring independent of the blood sugar improvement," Dr. Gupta says.

In 2016, the FDA granted a new indication for Jardiance—to reduce the risk of cardiovascular disease-related deaths in adult patients with both heart disease and type 2 diabetes.6

GLP-1s have been shown to reduce cardiovascular death and heart disease events such as heart attack and stroke.7 Among the studies demonstrating this benefit—A study of more than 9,300 patients followed for nearly four years with half the participants were given liraglutide (Victoza) and the other half getting a placebo. All patients had at least one cardiovascular condition such as coronary heart disease.7

The researchers looked at the rate of death in patients with T2D who had had at least one cardiovascular event, nonfatal heart attack, or stroke, and compared those on the Victoza with patients receiving the placebo. The rates of all adverse CVD outcomes were lower in patients who were on the medication.

In 2013, the FDA removed some of the restriction for prescribing and dispensing rosiglitazone. This was after a 2009 study, the Results of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study did not suggest an increased risk of excess cardiovascular risk.

However, Dr. Gupta says she thinks it should be used with caution. "I think the damage to its reputation has been done." However, any concern about patient risk for kidney disease must be considered in treatment planning.

Another turning point in diabetes management came in 2017; the FDA OK'd a new indication for liraglutide (Victoza), meaning this diabetes medication was approved for the reduction in the risks of all major adverse heart disease-related events in adults.8

Results of yet another study on the SGLT-2 inhibitor, ertugliflozin, is expected in 2020, Dr. Gupta says.

Another common diabetes treatment class, dipeptidyl peptidase-4 (DPP-4), are considered ''neutral" for cardiovascular risk,” she says. Examples of DPP-4s are sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta) and alogliptin (Nesina). They increase levels of the incretin, which are responsible for stimulating the release of insulin, inhibit the production of glucagon, and reduce gastric emptying, all of which help to regulate blood glucose levels.

When Advised to Take Another Medication Follow Your Doctors Orders

The program summarized very well the current debate about treating diabetes, says Matthew Freeby, MD, an endocrinologist at UCLA Medical Center, Santa Monica, and director of the Gonda Diabetes Center, UCLA David Geffen School of Medicine, who presided over the conference.

Doctors know that chronically elevated blood sugars increase small blood vessel (microvascular) complications to the eyes, kidneys, and feet, Dr. Freeby says. If diabetes is well-controlled over the years, the risks associated with this problem are vastly reduced. "Yet people living with diabetes are also at high risk for cardiovascular disease, specifically heart attack and stroke, which needs similar attention.”

Findings from the new studies focusing on heart disease outcomes related to diabetes medicines have shown that two classes—the GLP-1 receptor agonists and the SGLT-2 inhibitors—have positive effects on heart health, reducing risks of stroke and death from CVD. In addition, the SGLT-2s have demonstrated to provide a decrease in rates of hospitalizations for patients with heart failure, he says.

While pioglitazone (Actos) has been shown to reduce stroke risk, he says, there is little data to suggest other classes of medications have such positive heart disease benefits. "Therefore, organizations such as the American Diabetes Association are recommending the use of GLP-1 receptor agonists and SGLT-2 inhibitors for those living with heart disease or at high risk [of it]."

While the standard of care for a patient with type 2 diabetes is to receive instructions on lifestyle —adopting a Mediterranean-style diet and daily physical activity—and begin with taking metformin, doctors are now understanding better to benefits of adding one of these new classes of medications earlier, such as second-line therapies with metformin, Dr. Freeby says.

"People living with diabetes should discuss the potential risks and benefits of these medications with their provider," he says, and to understand what other risks you are facing to select the right medication to help you improve blood glucose control, protect your heart health, avoid weight gain (or support sustainable weight loss), and consider any other health risks that may impact your overall health.

The most important point may be that when your doctor recommendations that you add a second (or third) medication, you understand its importance and you take it regularly; if you have any concerns about taking any prescribed medication, including the cost, you should mention this to your doctor so you can be sure you are managing your health wisely.

The doctors have no financial disclosures regarding this presentation.

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