Diabetes Forecast

Some Type 2 Meds Help Prevent Heart Problems

What you need to know about a new crop of type 2 drugs and their benefits to heart health

By Andrew Curry , , ,

Stitchwork by Heather Solberg

In 2010, cardiologist Steve Marso, MD, helped organize a massive trial of the diabetes drug liraglutide. Researchers already knew it could reduce blood glucose levels, but new Food and Drug Administration (FDA) rules required them to make sure it was also safe for the heart before it was recommended as a diabetes treatment.
The study—nicknamed LEADER, for Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—was huge, complex, and expensive. It involved 9,340 people with type 2 diabetes at high risk for cardiovascular events and 410 hospitals, clinics, and research centers in 32 countries. Half of the patients were given a placebo; the other half took liraglutide.

Neither the participants nor their doctors knew who was getting medication and who wasn’t. Meanwhile, their heart health was tracked closely for almost four years.

The ambitious study’s goal was modest. “The trial was initially launched just to test for safety,” says Marso, now the medical director of cardiovascular services at HCA Midwest in Kansas City, Missouri. “Nobody was very optimistic the clinical trials would show a benefit.”

At the end of the study, Marso and his collaborators were surprised by the results (eventually published in 2016 in The New England Journal of Medicine): Participants who took liraglutide were slightly less likely to have a heart attack or stroke than those who took the placebo. They were also less likely to die from cardiovascular disease. “In 2018, we can say we now have therapies to improve the lives of people with diabetes and their cardiac health,” Marso says. “We’ve never had that before.”

Twist of Fate

The discovery of heart benefits for type 2 meds such as liraglutide was something of an accident. More than a decade ago, clinical trials for diabetes drugs typically lasted six months, and drug companies weren’t required to study the long-term cardiovascular risks. In fact, participants with a history of cardiovascular disease were often excluded from drug trials.

But then a 2007 study sparked controversy—and a major change to the drug approval process—when it claimed the blood glucose–lowering drug rosiglitazone (Avandia) increased the risk of heart attack and cardiovascular death. (The drug was restricted for years, although later studies showed no increased risk for heart attack.) As a result, the FDA put in place a fresh set of rules requiring new diabetes medications to be thoroughly tested to make sure they didn’t increase the risk of heart attacks or strokes in people with diabetes.

In the decade since, the data that emerged turned out to be a positive surprise. “When the FDA required all new drugs to be monitored for cardiovascular outcomes, lo and behold, the studies showed that several of these diabetes drugs had benefits for cardiovascular health,” says Om Ganda, MD, director of the Lipid Clinic at the Joslin Diabetes Center in Boston. “It’s a whole new chapter we’ve seen develop in the past few years.”

Healthy Ticker

If you have type 2 diabetes and have been diagnosed with cardiovascular disease, there are three types of drugs you should know about:

SGLT-2 inhibitors »
The class includes the oral medications empagliflozin (Jardiance), canagliflozin (Invokana), and dapagliflozin (Farxiga). They lower blood glucose by preventing the kidneys from reabsorbing glucose. Instead, glucose is released into the urine, where it’s passed out of the body. Drug trials have shown that sodium-glucose cotransporter-2 (SGLT-2) inhibitors affect cardiovascular risks (data on dapagliflozin’s benefits is newer and less robust, however). A study published in The New England Journal of Medicine in 2015, for instance, found significantly lower rates of death from cardiovascular disease in those who took empagliflozin versus a placebo.

Metformin »
This type 2 medication lowers the amount of glucose produced by the liver, which in turn helps lower blood glucose. The landmark United Kingdom Prospective Diabetes Study, published in The Lancet in 1999, drew a link between metformin use and cardiovascular benefits. And in 2016, Johns Hopkins University primary care physician and researcher Nisa Maruthur, MD, MHS, evaluated hundreds of smaller studies and concluded that, compared with sulfonylureas (another common class of type 2 diabetes drugs), metformin was associated with a significantly better reduction in heart attack risk.

GLP-1 receptor agonists »
Glucagon-like peptide-1 (GLP-1) receptor agonists—including liraglutide (Victoza), dulaglutide (Trulicity), exenatide (Byetta), and others—are designed to reduce blood glucose by stimulating receptors on specialized insulin-producing cells in the pancreas, encouraging them to produce more insulin. In a series of drug trials, including the LEADER study Marso helped put together, GLP-1 receptor agonists, which are typically injected once daily to once a week, reduced the risk of heart attack, stroke, and heart disease–related death by 10 percent or more.

Future Thinking

Maruthur and others are quick to point out that it’s still early days for both SGLT-2 inhibitors and GLP-1 receptor agonists. “We don’t know the biologic mechanism by which either reduces the risk of cardiovascular disease,” she says. Researchers know that they fight heart disease, in other words, but they still need to figure out how. That knowledge could help develop even better treatments or determine who stands to benefit the most from the existing drugs.

And unlike metformin, which has been in use for decades, not much is known about the long-term side effects of these medications, most of which have been available for less than a decade. For patients with diabetes and cardiovascular disease, the heart benefits probably outweigh any tiny added risks. “Newer isn’t always better,” Maruthur says. “But if you have cardiovascular disease, you should be considering them.”

If your doctor doesn’t recommend these type 2 medications for you, don’t worry. There are other things you can do to lower cardiovascular risk factors, including managing your blood glucose, cholesterol, and blood pressure. Regular exercise and healthy eating also go a long way toward ensuring your ticker is in tip-top shape.

Diabetes and Your Heart

The link between certain type 2 medications and cardiovascular benefits is welcome news. The most common causes of death for adults with diabetes are heart attacks and strokes. “It’s well established that diabetes is a major cardiovascular risk factor,” says Om Ganda, MD, director of the Lipid Clinic at the Joslin Diabetes Center in Boston. “It increases cardiovascular risk two- to fourfold.”

The Link

The connections between diabetes and heart disease work on several levels. There’s evidence that high blood glucose damages the lining of the major blood vessels over time. The stiffening that results is called atherosclerosis, and it’s a major cause of heart attacks and strokes. At the same time, people with diabetes are more likely to have a collection of other conditions—high blood pressure, obesity, and high cholesterol—that make heart disease worse. And conditions such as nerve damage can make exercise difficult, which raises cardiovascular risks.

The Research

The close connection between diabetes and heart disease has been a focus of research for decades. One key question has been the importance of tight blood glucose management to heart health. At one time, doctors thought the connection was iffy at best. It took a study called the Epidemiology of Diabetes Interventions and Complications to really turn the cardiology community’s thinking around. Researchers followed over 1,400 people with type 1 diabetes, all of whom had participated in the Diabetes Control and Complications Trial from 1983 to 1993. Long-term follow-up with the study’s participants revealed two major findings: People who kept their A1C under 7 percent had a reduction in cardiovascular events, and those cardiovascular benefits often took years (even decades) to show up. Long-term follow-up to the 1999 United Kingdom Prospective Diabetes Study found similar cardiovascular benefits of tighter blood glucose management in people with type 2 diabetes, though those benefits also took years to appear. In short, good diabetes management seems to have long-term heart benefits, even if it takes a while for those benefits to appear. 

The Goldilocks Solution

Managing your blood glucose is important for your heart health, but experts say there are some reasons people shouldn’t get too stringent with their blood glucose goals. “There’s now a lot of debate in different medical communities as to what’s our best target,” says Thomas Maddox, MD, MSc, a professor of cardiology at the Washington University School of Medicine. Older adults with type 2 diabetes and preexisting heart disease, for example, might want to relax their blood glucose goals a bit to avoid hypoglycemia and the dangers associated with it. Younger people with type 1 or type 2  might be better served keeping their A1C on the lower end of the recommended range to avoid long-term damage to the heart from high blood glucose.

“We talk to patients about ‘the Goldilocks solution,’ ” Maddox says. “Control, but not so tightly you’re dropping your blood sugar too low and getting in trouble.”



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