Diabetes Drugs: The Latest Good -- and Bad -- News

LEADER and EMPA-REG Trial Updates, and an FDA Warning About Renal Risks

Anne L. Peters, MD


August 16, 2016

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Today I am going to talk about two topics. First, I am going to discuss the results from the LEADER trial looking at liraglutide in terms of cardiovascular (CV) risk reduction in patients with type 2 diabetes. Then I am going to talk about the somewhat confusing world of sodium/glucose cotransporter 2 (SGLT2) inhibitors and their effect on renal function.

LEADER[1] was a big CV outcomes trial that looked at liraglutide at its nearly highest dose—the average dose was close to 1.8 mg/day—compared with placebo in about 9300 patients followed worldwide for 3.8 years. They were looking to see whether liraglutide was safe in terms of CV events.

Liraglutide did better than just being safe; it improved outcomes. There was a statistically significant reduction of about 12% in the major adverse cardiovascular events (MACE) outcome, which consisted of CV death, nonfatal myocardial infarction, and nonfatal stroke. There was a 22% very significant risk reduction in CV mortality.

This is the second big—and very significant—CV outcomes trial showing that a type 2 diabetes drug also reduces the risk for CV death.

Comparing LEADER With EMPA-REG

Results in the LEADER trial with liraglutide were different from those in the EMPA-REG[2] trial with empagliflozin, which is an SGLT2 inhibitor. Unlike the EMPA-REG trial, benefits did not start right away. You did not see a reduction in events in the first few months; it took about a year before the lines started to diverge.

The glucagon-like peptide 1 (GLP1) receptor agonist seems to be working differently than the SGLT2 inhibitor in terms of CV risk reduction. Also, as expected, there was not a reduction in the risk for congestive heart failure hospitalization. This is again a difference between the two drugs: One is more like a diuretic, and one works through an entirely different mechanism.

A difference in the LEADER study compared with other trials was that patients started out with a very high baseline A1c of around 8.5%. They improved when started on liraglutide, but not so much with placebo. In the placebo arm, many more patients required the addition of insulin.

There was not an increase in pancreatitis in patients who were on liraglutide. But there was, as expected, an increase in gastrointestinal side effects, which we know are part and parcel of the use of GLP1 receptor agonists.

Again, this was a very important finding—that a diabetes drug not only reduces blood glucose levels, but also lowers CV disease risk. It is very comforting, to say the least, that these agents do not worsen the risk and, in fact, improve the outcomes in our very high-risk patients.

Conflicting News About Renal Effects

In terms of SGLT2 inhibitors, at the American Diabetes Association meetings where the LEADER trial results were presented, there were great data on renal function in EMPA-REG. In EMPA-REG, empagliflozin not only reduced CV risk, it helped prevent deterioration of renal function. It very significantly reduced the risk for patients developing and progressing in terms of renal failure.

This was an incredibly good finding. A lot of my patients and colleagues have been concerned that a drug that acts on the kidneys may worsen kidney function, yet in the EMPA-REG trial, there was an actual benefit in renal function.

At basically the same time, the US Food and Drug Administration (FDA) announced a new warning based on an increase in the risk for acute renal failure in about 100 patients treated with canagliflozin or dapagliflozin. The highest-risk patients were those who you might expect to be at highest risk: They were patients who had more risk for volume depletion and patients on diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or nonsteroidal anti-inflammatory drugs.

These cases of renal failure could be quite serious. It was not that many cases, but the FDA data are from case reports, so we do not know how common this is.

Clearly, what the FDA seems to be saying is that acutely, there may be a risk for worsening renal function with these agents. When you put a patient [on an SGLT2 inhibitor] who is already on a diuretic, who already has some degree of hypovolemia and who may be at risk for dehydration, you can actually cause acute renal failure.

Take-Home Messages

Be cautious. Make sure that you check renal function before you start an SGLT2 inhibitor, and follow the prescribing guidelines for these agents.

If a patient develops signs or symptoms of renal dysfunction, check another creatinine level to make sure your patient is safe.

The majority of patients will do well, but obviously it is important to know about this side effect. Know that most of your patients are going to benefit long-term from being on an SGLT2 inhibitor. But acutely, you may find patients who have significant renal dysfunction, and you need to be on the alert for them.


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