There’s an emerging consensus that now may be the time for cardiologists to start thinking seriously about prescribing diabetes drugs. Until now most cardiologists have not considered this to be part of their job description. But now new data from large cardiovascular outcome trials (CVOTs) shows that these drugs may one day become, like statins and ACE inhibitors, key weapons in the fight to prevent cardiovascular events.
The revolution has its origins in the storm of controversy in the last decade over rosiglitazone, a once-popular glucose-lowering drug. At its core the controversy was provoked by safety concerns over the drug, and those concerns were fueled by the absence of any evidence showing a clinical benefit with the drug. The controversy helped put an end to the reliance on glucose lowering as a surrogate endpoint.
This uncertainty led the FDA in 2008 to establish new regulations requiring CVOTs to “demonstrate that the therapy will not result in an unacceptable increase in cardiovascular risk.” As a result the number of randomized patients skyrocketed. The CVOTs were designed to first demonstrate safety of the new diabetes drugs, so noninferiority was the main goal of the trials. Results from the first round of outcomes trials met the criteria for noninferiority and so were able to show show that there was not an increase in overall CV risk.
But it was the secondary goal of these trials that led to the transformation of the field. Baked into the trial design was the provision that if they were able to establish noninferiority then the trial investigators were permitted to test for superiority. The second phase began when Empa-Reg became the first trial to convincingly show a clear benefit, including a reduction in cardiovascular death and a reduction in hospitalization for HF. with empagliflozin (Jardiance, Boehringer Ingelheim). Then, more recently, the LEADER trial showed a significant reduction in cardiovascular events with liraglutide (Victoza, Novo Nordisk). In both trials nearly all the patients had significant established cardiovascular disease– precisely the population that cardiologists are likely to see.
Darren McGuire, UT Southwestern, has long been interested in the intersection of cardiovascular disease and diabetes. At a recent talk at the American Diabetes Association meeting McGuire argued that the new diabetes drugs could have a clinical impact similar to that of statins and ACE inhibitors and ARBs. Although there are important differences in the trial populations, he noted that the NNT for diabetes drugs was in the same league: simvastatin with a NNT of 30 to prevent one death, ramipril with 56, empagliflozin with 39.
McGuire said the Empa Reg results “are paradigm shifting” and have a “magnitude of effects on key outcomes of CV death and HF that are unprecedented for cardiovascular therapies.” From the cardiologist’s perspective, he said, “empagliflozin is a potent cardiovascular medication with favorable side effects of glucose, BP, and weight reduction.”
He noted that, like statins, empagliflozin is easy to use and has few side effects. It may be a bit easier to incorporate into clinical practice than liraglutide, notes McGuire. “Initiating an injectable like liraglutide is a bit more of a stretch for cardiology practices, but as we gain some experience with PCSK9 inhibitors that may become less of a hurdle,” he said.
Steve Nissen (Cleveland Clinic) is another strong advocate for cardiologists treating patients with type 2 diabetes with these drugs. Nissen was a central player in last decade’s rosiglitazone debate and helped create the FDA policy requiring cardiovascular outcome trials.
“There’s nothing about the drugs that prevents a cardiologist from prescribing” diabetes drugs, said Nissen. For patients with coronary heart disease “it doesn’t make sense to treat just one component, just the lipids.” Nissen said he was “delighted that we now have the evidence we’ve desperately needed.”
For cardiologists the decision to treat patients with diabetes drugs should be easy, said Nissen. “If I’m seeing the patient for CV disease then by definition that patient is suitable.” Cardiologists need to take action when it comes to cardiovascular risk,” he said.
Ethan Weiss (UCSF) said that the decision to treat patients with diabetes drugs has “lots of parallels” with the lipid story decades ago. “It is hard to remember, but lipids were the domain of endocrinologists until randomized controlled trials demonstrated that treating patients with CV disease or high CV risk with lipid lowering medications (statins) reduced the risk of CV disease.”
“The association between T2DM and risk of CV disease has been known forever just as it was with lipids. But now that there are RCTs showing real CV risk reduction with diabetes drugs, will there be a similar shift in prescribing practices for diabetes medications? I’m not sure, but I would guess yes.”
But he warned that the transformation will not be simple. “Just as not all drugs that lower LDL will reduce CV risk, not all drugs that lower A1C will lower CV risk.” Cardiologists, said Weiss, “recognized (mostly) that the primary goal of lipid lowering therapies (statins) was not to treat high LDL but to reduce CV risk. In the case of diabetes drugs, there may be a similar principle in play. That is, cardiologists will have to be focused on CV risk reduction, not A1C lowering per se.”
Weiss also wondered about the role of primary care. “Shouldn’t this all just be the domain of the primary care doctor? Ideally yes. But the same could be said for blood pressure treatment or even treatment with statins.”
A more difficult problem will be what to do about “pre-diabetes,” since there is no evidence so far, and, as Weiss notes, “it is difficult to accurately define who has pre-diabetes.” Undoubtedly the issues of cost and the risk/benefit ratio will need to be carefully scrutinized in this lower risk population.
Kevin S Shah, a cardiology fellow at UCLA, acknowledged that “it’s never my first instinct to scrutinize my patients’ diabetes medication regimens.” With the new data on empagliflozin and liraglutide, however, he’s “paying closer attention.” If the endocrinologists or primary care providers aren’t giving these agents then “it makes sense for cardiologists to consider doing so. Since we are the primary consumers of the literature showing their potential in population with cardiovascular disease, it’s not unreasonable to consider incorporating them in our practices.”
Guidelines may prove an important factor in driving the use of these drugs. McGuire said that “empagliflozin and liraglutide should now enter the CV guidelines for treatment of patients with type 2 diabetes and prevalent atherosclerosis.” He said that we need “further data” to support a class effect. “And figuring out how individual patients and society will afford such application of the evidence-basis will be the key consideration for such guideline evolution and application.”