COMMENTARY

'Game Changer': Treat Diabetes and Also Reduce CV Risk

'We Are Finally Seeing the Results'

Jay H. Shubrook, DO; James J. Chamberlain, MD

Disclosures

February 09, 2018

Jay H. Shubrook, DO: Hi. I'm Jay Shubrook, DO, family physician, diabetologist, and professor at Touro University, California. We are continuing our series, Everyday Diabetes: Practical Management Strategies for Primary Care.

I'm delighted to have Dr Jim Chamberlain today. He is the medical director of diabetes services at St Mark's Hospital and St Mark's Diabetes Center in Salt Lake City, Utah. He is also an active contributor to the Primary Care Advisory Group for the American Diabetes Association.

James J. Chamberlain, MD: Thanks for having me, Jay.

Dr Shubrook: There has been a lot of news about diabetes medications and cardiovascular (CV) outcomes trials. It seems to be a change in trajectory. Why do I need to know about CV outcomes trials?

Importance of CV Outcomes Trials

Dr Chamberlain: We have had good results lately. It's something that we have been trying to accomplish for a long time, and we are finally seeing the results we want to see.

Before we get into some of the data, I want to introduce the term MACE (major adverse cardiovascular events). The US Food and Drug Administration (FDA) has required that all new diabetes medications coming on the market prove CV safety.

Two trials recently showed benefit with respect to CV outcomes. The first was the EMPA-REG trial,[1] which was the study of empagliflozin (Jardiance®). With over 7000 patients and over 3 years of data, patients in the trial met the composite endpoint of a reduction in MACE (CV death, nonfatal myocardial infarction[MI], nonfatal stroke) by 14%. Most of that was driven by a huge CV death risk reduction of 38%. That indication is now included on the FDA-approved label for empagliflozin.

The second was the LEADER trial[2] with liraglutide (Victoza®). This was a bigger study of over 9000 patients and 3-4 years of data. The researchers found a 13% relative risk reduction in the composite endpoint of MACE. Liraglutide now has that composite endpoint outcome indication from the FDA: risk reduction from cardiovascular death, nonfatal MI, nonfatal stroke.

This is why it's in the news. Prior to these studies, our CV information was from the ACCORD trial,[3] the ADVANCE trial,[4] and the Veterans Affairs Diabetes trial (VADT),[5] none of which found an improvement in CV outcomes or mortality with aggressive glycemic control. In the ACCORD trial, we were harming people; there was a 22% increase in mortality [associated with intensive glucose lowering] and the study was halted early.

Results in the older trials were probably driven by hypoglycemia, which is another topic. It's really important and exciting to have drugs that not only lower glucose but also lower blood pressure and body weight, and minimize the risk for hypoglycemia. With all of that we are seeing the benefit that we hoped we would see.

Consider Cardiovascular Risk

Dr Shubrook: I need to ask a more basic question. When I think of treating diabetes, I think about reducing blindness, kidney failure, and amputation. But should I be thinking about CV risk too?

Dr Chamberlain: It's a great question. Both are important .We think that microvascular complications are related, for the most part, to blood glucose—maybe blood pressure, too, with [the effect on] kidney function. There are also people who think that we should be judging drugs on their [associated] CV risk reduction and not A1c reduction; we all know that. So we have to look at both. We are trying to lower blood glucose not only to make people feel better, but also to reduce microvascular complications. And we have this whole other incredibly important endpoint that we need to be looking at, which is CV death, because people with diabetes die two to three times more frequently from CV disease than those without diabetes. We need to be looking at both; it's all important.

It's exciting that we can finally start to look at this CV risk-reduction side, separate from statins, aspirin, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and all of those things. We are looking at what we traditionally think of as glucose-lowering drugs also improving CV outcomes—which is pretty neat.

Dr Shubrook: Yes. That is so important because my patients do not think about CV disease; they think about these other endpoints. But as many of the listeners know, most of our patients actually die of heart disease and stroke.

We worry about these things, and microvascular [complications] are important, patient-focused endpoints. But we still need to work to prevent the number-one cause of death in people with diabetes.

Is Practice Changing?

Dr Shubrook: How has this new information affected your practice? Does it change the way you prescribe? Does it change the classes you use?

Dr Chamberlain: Yes, it is [changing the way we prescribe]. Now that we have drugs—the glucagonlike peptide-1 (GLP-1) agonists and sodium glucose cotransporter-2 (SGLT-2) inhibitors—with some data behind them, it's a little hard not to use these drugs earlier in place of traditional drugs like thiazolidinediones (and maybe insulin), which cause weight gain, and sulfonylureas, which cause hypoglycemia. Those are probably the side effects that have limited our ability to reduce CV events in some of these [earlier] outcomes trials.

When I am working with a patient who is not at goal, and we are choosing a second, third, or fourth drug, I absolutely think more about these outcomes trials and the data that we have that support a few of these drugs.

Dr Shubrook: Are you able to get these covered in your practice?

Dr Chamberlain: Typically, yes. It may not be the one I want necessarily but at least one in the class. One of the things that comes up is the question of whether this [reduction in CV risk] is a class effect. For example, Canagliflozin (Invokana®) had a CV safety trial[6] that did not show the same sort of major adverse CV event risk reduction found with empagliflozin. Some of the dipeptidyl peptidase 4 (DPP-4) inhibitors did not show benefit but did not show harm. I try to find a GLP-1 agonist or SGLT2 inhibitor that I like to use more frequently and earlier, but you cannot always get the one you want covered. You need to figure out how much time you want to spend fighting that fight.

Salient Points

Dr Shubrook: For the busy primary care provider, what are two or three things they should know relating to the new medications and CV outcomes?

Dr Chamberlain: Number one, be aware. Know that we have data now. Multiple drugs now have indications from the FDA to reduce CV risk.

The second thing is to understand who was studied and who that indication is for. It's for patients with type 2 diabetes who have established CV disease. It's not for everybody with type 2 diabetes. Do not expect that you are going to get CV risk reduction with a 40-year-old patient with type 2 diabetes who does not have vascular disease and who may have no other CV risk factors. That is not who was studied.

The third is, you need to know these drugs. This is really important. Recently, there have been some concerns with SGLT2 inhibitors and lower-extremity amputation. SGLT2 inhibitors are great and powerful drugs, but they're not necessarily better for glycemic control because they are pretty average. They give us the 1% A1c reduction we like, but they volume-contract—it's like being on a diuretic and a diabetes drug at the same time. The potential amputation risk may be from volume contraction, intravascular volume depletion in people who may have peripheral vascular disease that is undiagnosed. It's really important that primary care providers be aware of this. Look at people's feet. The risk factors for amputation in the CANVAS trial[6] were previous amputation, history of ulceration, peripheral sensory neuropathy, and peripheral vascular disease.

You need to know the warnings with the drugs. You have to know the dosing restrictions based on glomerular filtration rate. Especially with SGLT2 inhibitors, we need to be looking at people's feet when we prescribe these drugs. Seriously—you should look at people's feet and say, "Okay, you have no neuropathy, you have good pulses and no known vascular diseases. It's probably a safe drug for you." Again, SGLT2 inhibitors are great drugs, but you really have to look at several different clinical factors when you prescribe them.

Dr Shubrook: Thank you so much. You highlighted a couple of important things. Number one: The game has changed. We now have medications that not only lower glucose, but they also lower the number-one cause of things that kill people with type 2 diabetes. Number two: Get to know the GLP-1 receptor agonists and the SGLT2 inhibitors. Number three: Continue to try to pick agents that reduce not only microvascular risk but also macrovascular risk. Be aware and know the medications for their good effects, their side effects, and also their net effects on glucose.

Dr Chamberlain: Could not have said it better. Thanks, Jay.

Dr Shubrook: Thank you so much. We are really glad that you could contribute to the program.

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