Robert Eckel, MD

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August 21, 2017

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Hi. I'm Dr Robert Eckel from the University of Colorado Anschutz Medical Campus at Aurora, just outside of Denver. I'm here at the American Diabetes Association Meeting. I had the privilege of moderating a session that dealt with new information about the use of alirocumab, one of the newer proprotein convertase subtilisin kexin 9 (PCSK9) inhibitor drugs on the market, and its impact on diabetes.

We know that there is a relationship between lipids and cardiovascular disease in patients with diabetes. But most of the time, patients with diabetes do not present with high levels of low-density lipoprotein (LDL) cholesterol, which is the indication that the US Food and Drug Administration (FDA) put forth for use of PCSK9 inhibitors.

Non-HDL Cholesterol Outcomes in Diabetes

This series of studies[1] presented new information on patients mostly with type 2 diabetes, in which the outcome was based on the reduction of non–high-density lipoprotein (HDL) cholesterol. This is really important because the current American Heart Association and American College of Cardiology guidelines[2] reflect LDL cholesterol as the treatment variable, not non-HDL cholesterol. This is a new twist, and an important one, because lipid disturbances in diabetes relate more to triglycerides and lower levels of HDL cholesterol.

Think of the math here: If we take HDL cholesterol (which tends to be low in patients with type 2 diabetes), triglycerides (which tend to be high), and LDL cholesterol (which may be calculated as normal or reaching goal) and we subtract a low HDL from a higher total cholesterol (which includes the triglycerides divided by 5), ultimately the non-HDL cholesterol may be a much more important factor for favorably modifying in patients with type 2 diabetes—and less commonly in type 1 diabetes—to reduce cardiovascular disease risk.

ODYSSEY DM-Insulin Study

The approach in the ODYSSEY DM-Insulin study[3] related to a twofold stepwise modification of non-HDL cholesterol in patients with type 1 and type 2 diabetes. Almost 100% of the patients in the study were treated with insulin.

I had to pause there for a second. Why would less than 100% have insulin-treated diabetes if the intent was to look at the impact in patients with insulin-treated diabetes? There must have been a dropout early or something, because 99%+ were on insulin.

Nevertheless, a dose-escalation platform was used for the alirocumab intervention: 75 mg every 2 weeks initially, with escalation to 150 mg/dL if the goals for LDL lowering were not achieved.

We saw a benefit in lowering non-HDL cholesterol. A large majority of patients, mostly with type 2 diabetes, achieved a non-HDL cholesterol of under 100 mg/dL. If I remember accurately, the baseline level was around 130 mg/dL—30 mg/dL above that theoretical treatment goal, which would maximize benefit for reduction of risk.

ODYSSEY DM-Dyslipidemia Study

The second study, ODYSSEY DM-Dyslipidemia,[4] looked at patients with mixed dyslipidemia and type 2 diabetes. Here, only about half of the patients were treated with insulin.

Now we are looking at people whose triglycerides were above 150 mg/dL and whose non-HDL cholesterols were clearly above 130 mg/dL—really, a level of almost 150 mg/dL. This is a group we commonly see in practice. In my lipid clinic at the University of Colorado Hospital, it's not uncommon for patients with diabetes to be referred whose LDL cholesterol is pretty normal, triglycerides are up, and HDL is low. Therefore, their non-HDL cholesterol is elevated.

This study had the same type of design, whereby a usual-care group was compared with an alirocumab-treated group. The dose was escalated from 75 mg to 150 mg as needed to target the outcome variable of LDL cholesterol < 70 mg/dL to see the impact on these atherogenic lipoproteins. Again, we saw highly favorable data indicating that 75 mg of alirocumab, increasing to 150 mg in some patients, every 2 weeks was successful in lowering non-HDL cholesterol to the treatment goal of < 100 mg/dL.

Clinical Impact

Let's pause here a second. How important is a study like this?

Keep in mind that some of these patients would have met the current criteria for treatment of LDL cholesterol if the practicing physician felt that their LDL had not been sufficiently lowered if they had had a previous heart attack or stroke. Many of these people had not had a heart attack and would not have met the FDA criteria for a PCSK9 inhibitor.

What we have is a new look at the more commonly evolved lipid disorder in patients with type 2 diabetes and, again, less so in type 1 diabetes. We have learned that if non-HDL cholesterol is a goal and we are not meeting it with other therapies, then the PCSK9 inhibitor may be an option for therapy.

One thing that bothers me a little bit in terms of concluding that we should be more aggressive here is that this is not an outcomes study. This was simply an intervention that proved successful in modifying a risk factor, which some people don't consider to be as important as LDL. The other thing to take home from this is that these patients were treated with a minimum number of lipid-altering medications other than statins. Most of the people were on statins—some 80%-90% in the two trials—but some of them were on ezetimibe, a fibrate, or niacin, other drugs that we might use to lower lipids.

Take-Home Points

Does the clinician step forward to use a drug even if indicated with a history of a myocardial infarction or stroke? At this time, I don't think so.

The second important issue is, again, this was not an outcomes trial. These types of data beg for an outcomes trial to be carried out in patients with insulin-treated or non-insulin-treated diabetes with mixed dyslipidemia to prove the long-term benefit of such a major modification on atherogenic lipids and lipoproteins.

Thank you very much for tuning in and for your attention.

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