The unrelenting growth of diabetes around the world is prompting cardiologists to rethink how they treat and manage a challenging patient population, even as an emerging class of cardio-protective diabetes drugs is setting the stage for transformation.
Nearly ten years ago, a Food and Drug Administration (FDA) advisory panel expressed concern that several novel diabetes therapies carried an increased or at least ambiguous cardiovascular risk and recommended safety testing on all new diabetes drugs. At the time, a number of industry experts predicted that this new guidance would put a chill on the development of glucose-lowering medications for millions of individuals with diabetes. The opposite has occurred. Instead, it touched off a wave cardiovascular outcomes trials that led to the serendipitous discovery of newer classes of type 2 diabetes drugs that not only impact blood glucose levels but, more importantly, can significantly reduce cardiovascular deaths and events. Given the lockstep pathology of diabetes and cardiovascular disease—at least 68 percent of people age 65 and older with diabetes will die from some form of heart disease, according to the American Heart Association, and adults with diabetes are two to four times more likely to die from heart disease than those without it—the emerging data from these studies were impossible for the cardiovascular community to ignore.
The repercussions go well beyond medications, however. The new cardio-protective drugs are raising fundamental questions about how cardiologists have traditionally managed a patient population that for many comprises half or more of their practice. Should they take a more proactive role, for example, in secondary prevention, knowing how easily hypertension, abnormal cholesterol and triglycerides, obesity and lack of physical activity can escalate to cardiovascular morbidity and death? Moreover, should they reflexively hand off diabetic patients (“Sorry, that’s not my area of expertise”) to endocrinologists and diabetologists, or attempt to forge a closer partnership with these specialists to ensure optimal care for a highly vulnerable patient set?
“It’s not necessarily the cardiologist’s role to deal with blood glucose, but it’s absolutely front and center for us to use medicines in people with type 2 diabetes that have proven cardiovascular benefits, particularly if it means reducing cardiovascular deaths,” says Mikhail Kosiborod, MD, director of cardiometabolic research at Saint Luke’s Mid America Heart Institute in Kansas City, Mo., and professor of medicine at the University of Missouri-Kansas City. “And it’s also our responsibility to work more actively with endocrinologists and our primary care colleagues to lower cardiovascular risk in patients with diabetes and established cardiac conditions.”
New treatment protocols
That diabetes and cardiology are intersecting in meaningful new ways was evident at the American College of Cardiology (ACC) 2017 Scientific Session in Washington, D.C., where novel diabetes treatments held center stage. “They certainly add a new page to the playbook with respect to therapies we might consider for the reduction of cardiovascular risk in diabetic patients,” says James Januzzi, MD, a cardiologist at Massachusetts General Hospital in Boston and moderator of several ACC.17 panel discussions focused on these new classes of therapies. “Instead of just throwing drugs at patients to manage their blood sugar, we’re now seeing we might be able to actually reduce cardiovascular risk.”
To reinforce the point, several months later, the ACC issued a statement co-authored by Januzzi that called on cardiologists to “familiarize themselves with diabetes drug classes with [cardiovascular] benefits as many of their patients (i.e., type 2 diabetes plus [cardiovascular] disease) could benefit from their use” (J Am Coll Cardiol 2017;69:2646-56). Significantly, the ACC also opined that collaboration among cardiologists, primary care physicians and diabetologists will be necessary in the future to achieve optimal treatment goals for diabetic patients.
The profound impact of diabetes on ischemic heart disease has been known for years, of course, and is influencing how growing numbers of cardiac specialists screen and treat their patients. Knowing that people with diabetes face the same risk of dying from a heart attack as someone who has already experienced such an event, they have begun holding them to a stricter set of guidelines, such as starting treatment earlier and addressing high blood pressure and high cholesterol more aggressively than they would for nondiabetic patients. “When we see a patient for cardiac catheterization or PCI, their diabetic state is a major part of the conversation, both with our colleagues and patients themselves,” says Sunil Rao, MD, section chief of cardiology at Durham VA Medical Center in Durham, N.C. “I think cardiologists are becoming even more aware of the metabolic syndrome or prediabetic state so that we can encourage patients to adopt preventive therapies, like exercise and weight loss, so they don’t become diabetic.”
Some physicians, however, believe the tilt to diabetes needs to go much further. “I would argue that the greatest unmet need in diabetes disease is to drive down cardiovascular morbidity and mortality,” says Steven Marso, MD, medical director of cardiovascular services for HCA Midwest Health in Kansas City, Mo., and an interventional cardiologist. “For that reason, I think the [treatment] guidelines need to be flipped and cardiovascular prevention, whether it’s primary or secondary, should be the major therapeutic goal.”
Until recently, metformin was the only drug that showed evidence of cardiovascular benefits for diabetic patients. Because it was considered safe and didn’t cause weight gain or increase the risk of hypoglycemia, metformin became widely used as a first-line therapy for diabetes patients with cardiovascular disease. Over the past four years, however, several new classes of drugs have emerged from a flurry of outcomes trials and are beginning to reconfigure the therapeutic landscape. Among those making the biggest splash are sodium glucose cotransporter 2 (SGLT2) inhibitors and GLP-1 receptor agonists. The EMPAREG OUTCOME trial fired the initial salvo, demonstrating that the SGLT2 inhibitor empagliflozin (Jardiance; Boehringer Ingelheim) reduced the risk for cardiovascular death by 38 percent and the risk of hospitalization for heart failure by 35 percent (N Engl J Med 2015;373[22]:2117-28).
Nova Nordisk’s GLP-1 receptor agonists liraglutide (Victoza) and semaglutide (Ozempic) also reduced cardiovascular death and major events, but more slowly than SGLT2 inhibitors and without affecting heart failure risk. The LEADER trial demonstrated that liraglutide reduced by 13 percent the rates of cardiovascular events and mortality. It also reduced A1c levels and hypoglycemic events and led to weight loss in a significant number of patients (N Engl J Med 2016;375[4]:311-22). As a result of the LEADER study, the FDA approved in August 2017 a new indication for Victoza—first introduced in 2010 for patients with type 2 diabetes—to reduce the risk of major cardiovascular events, heart attack, stroke and cardiovascular death in adults with type 2 diabetes and established cardiovascular disease.
Other clinical trials of diabetes medications that confer cardiovascular benefits are underway, involving numbers of patients never before seen in diabetes studies. Among the intriguing questions researchers will attempt to answer: can agents like SGLT2 inhibitors and GLP-1 receptor agonists prevent deaths and cardiac events in people with cardiovascular conditions who don’t have diabetes? None of the drugs approved to date in those classes carry that indication, but researchers suspect further studies will show the answer to be yes.
Winning over a skeptical community
Despite the eye-catching data that have already emerged from studies of cardio-diabetes drugs, winning over a broad cardiology community that’s by nature leery of diabetes drugs (like sulfonylureas, which carry a black box cardiovascular warning from the FDA) with the potential to actually increase cardiovascular risk could be an uphill battle. Conceding there may be some hesitancy by cardiologists to use SGLT2 inhibitors and GLP-1 receptor agonists, Januzzi sees parallels to the roll-out of another now-entrenched class of drugs. “When statins first came out, cardiologists looked at them with a similar degree of uncertainty and often relied on endocrinologists to prescribe them to lower blood cholesterol levels,” he points out. “It wasn’t until we recognized that these drugs also reduce cardiovascular risk that cardiologists assumed the responsibility of lipid lowering—and now own that concept rather substantially.”
How fast—or even if—history repeats itself remain an open question. “The challenge becomes which physicians and providers will commit time during their day to treat diabetes,” says Marso. “Very, very few cardiologists have taken a proactive approach to using diabetes therapies to reduce cardiovascular risk. I think the data [on the new agents] will change that.”
A far-reaching educational effort will be required for a statin-like shift to occur, in the view of many in the field. “Many clinicians are still not aware of the trial results,” observes Kosiborod, who splits his professional time between patient practice and evaluating new compounds that may improve cardiovascular outcomes in people with diabetes. “And of those who have seen the results, the question is whether they realize that we’re not talking just about glucose lowering here.”
The medical societies along with the cardiovascular community and industry have an obligation to spearhead any educational movement, according to some experts. This means informing and continually updating physicians on the efficacy, tolerability and safety profiles of the new agents and how to effectively integrate them into their professional practice. The ACC has taken a step in that direction with its preparation of a document that summarizes the broad range of approaches currently available to reduce cardiovascular risk in diabetic patients, including the latest therapies. That peer-reviewed statement, reportedly a year or two away from publication, is expected to establish consensus around evaluating and managing diabetic patients across the therapeutic realm of lipid lowering, blood pressure control and use of the latest cardioprotective agents.
The growth of preventive cardiology
The success of clinical research in churning out new medicines for diabetes is providing a backdrop for several other significant changes in the field, including the growth of preventive cardiology as well as multispecialty teams, on which cardiologists are integral players. Pointing out that some cardiac physicians have actively practiced preventive strategies for their diabetic patients for years, Rao (who has a family member with type 1 diabetes) believes more and more will be coming onboard. “Having a two-pronged approach where we do both primary and secondary prevention is going to have a much greater impact than just seeing a patient who’s had diabetes for years,” he says. “Now that we have more therapeutic options, I’m hopeful there will be more preventive cardiologists who specialize in diabetic patients.”
That thought is echoed by Marso, who has been the lead investigator of three published studies over the past year (including LEADER) evaluating new diabetes therapies for safety and efficacy. What he sees evolving is an expanding group of cardiologists dedicated to driving down risk in diabetes patients. “I think diabetes management will become an integral part of their practice, much like hyperlipidemia, hypertension and obesity have become part of their armamentarium,” he says. “I also believe these folks will be getting trained in diabetes management.” As others point out, preventive cardiologists are likely to be the first group to widely adopt the new diabetes therapies with cardiovascular benefits.
What’s also likely is that cardiologists focused on preventive measure will not be working in isolation. They will become part of collaborative teams—an approach already widely deployed in heart care settings—that include diabetologists, internal medicine specialists, interventional cardiologists, dieticians and other healthcare professionals who collectively provide comprehensive care. “Consider that patients with diabetes not only have cardiovascular disease, but may have peripheral vascular disease, renal disease and other comorbidities, which intersect to heighten their overall cardiovascular risk,” explains Januzzi. “A team approach would include specialists in these various areas, together with a point person who would typically be the primary care provider.”
That model is already taking root at institutions and medical offices around the country. “My hope is that we’ll see many more of these collaborations as time goes on, with the main beneficiaries being people with diabetes who have a high risk of cardiac complications,” says Kosiborod. “We’ve already seen a great deal of collaboration when it comes to clinical research. It’s now time to extend that to clinical practice.”