March 18, 2018
Debating the benefits of ultra-low low-density lipoprotein (LDL) cholesterol versus a more reasonable, but still low, level among patients with diabetes, Steve Nissen, MD, of the Cleveland Clinic, Ohio, and Henry N Ginsberg, MD, Irving Professor of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, entertained delegates on March 17 here at ENDO 2018: The Endocrine Society Annual Meeting.
Starting the debate, Nissen argued his position. "There are few relationships in clinical medicine as linear as this. The benefits of LDL reduction are continuous and extend to extremely low levels," he said while showing slide after slide of the major statin trials, studies with ezetimibe, and finally recent trials with the PCSK9 inhibitors.
And, stressed Nissen, "In a lot of the trials, arguably the biggest benefit was seen in those with diabetes."
In response, Ginsberg said: "I agree with most of what Steve has said to you. Everything we know says that low LDL is better, so what could be bad? I think lowering LDL fairly aggressively is good, but how low can you really go?"
The Lower the Better? Large Regression of Atherosclerosis at Ultra-Low LDL
Nissen claims that LDL levels of 25 mg/dL "are good," and in the IMPROVE-IT trial with ezetimibe (Zetia, Merck), levels were driven as low as 15 mg/dL "and we saw massive regression of atherosclerosis. Less plaque equals less events."
"People on primitive diets running around the jungle have very low LDL levels and don't have cardiovascular events," he observed. "So there is no question in my mind that going from 70 to 30 mg/dL, for example, has incremental benefits."
But Ginsberg maintained that the biggest benefit in LDL lowering is seen when patients with very high levels get down to moderate levels — even, for example, dropping from 200 to 100 mg/dL, as seen in the 4S trial.
And without medication, Ginsberg said, "People who become vegans, who eat twigs and leaves, can get to 50 or 30 mg/dL, but they are few and far between."
"If we cut to the chase, we see that the average LDL of an American adult not on treatment is 130 mg/dL. If you put them on a high-dose statin, you can get that down to 70 to 80 mg/dL. If you add in ezetimibe, you can get it down to 50 mg/dL."
But, he wondered, "Are you going to get more benefit by dropping down to 20 mg/dL, or 15 mg/dL?"
Nissen concluded: "It's incontrovertible that lower LDL levels are better, but are they safe?"
He does acknowledge "that, particularly with intensive statin therapy, there is an increase in new-onset diabetes," but he argued that even with this, the benefit of lowering cardiovascular risk offsets the increased risk of new-onset diabetes.
"A slight change in blood sugar doesn't diminish the effects of lowering LDL. If you go from an HbA1c of 5.9% to 6.1%, you are going to be called 'diabetic'. But these patients get the same morbidity and mortality benefit [from LDL lowering], and I don't think you can make the case that the diabetes issue is a reason to undertreat," he stressed.
Noting that the effect of statins on new-onset diabetes was first observed in the JUPITER trial, Ginsberg conceded that "you can guess who will develop diabetes," and said it is individuals with prediabetes, metabolic syndrome, and insulin resistance who are most at risk.
What is less clear, he added, is whether this effect is specific to statins, or is it just related to intensive LDL lowering, so therefore could also be an issue with PSCK9 inhibitors?
Detailing a subgroup analysis of the FOURIER trial — which looked at subgroups by diabetes status and risk of new-onset diabetes with evolocumab (Repatha, Amgen) — Ginsberg noted that "HbA1c didn't change at all over a median follow-up of 2.5 years, but we need a lot more data. We don't have the numbers yet with PSCK9 inhibitors, or ezetimibe, to definitely answer this question."
'You Might Forget Your Car Keys, and Have to Sell Your House'
"Here the data are ... impressive and worrisome," he noted. In the SPARCL trial, for example, the hazard ratio was 1.66 for hemorrhagic stroke, with 55 events in the atorvastatin group versus 33 in the placebo group.
Next, discussion turned to neurocognitive defects, which have been claimed to be a side effect of intense lipid-lowering, or as Ginsberg put it, "you might forget your car keys, or no longer be able to give a lecture."
Nissen said he doesn't believe this to be an issue.
Describing the neurocognitive substudy of FOURIER with evolocumab, called EBBINGHAUS, he noted that there was "no effect [on neurocognition] of getting to these LDL levels of 15 mg/dL, and the trial was designed by the best neurologists."
"I don't think there is a shred of good quality evidence to suggest a neurocognitive defect," he emphasized, adding, "We reduce morbidity and mortality by driving down LDL as low as we can, but not at the cost of adverse events."
However, Ginsberg argued that EBBINGHAUS "is a very narrow look at cognition over a short period of time."
And he noted that in the very recently reported ODYSSEY Outcomes trial with another PSCK9 inhibitor, alirocumab (Praluent, Sanofi/Regeneron), 70% of patients going in were statin-naive, and the most "dramatic" benefit in all-cause mortality was "driven by those who had very high LDLs to start with."
Nissen argued however that ODYSSEY "was badly designed and badly executed, and it didn't add to our knowledge. The better trial is FOURIER, and the results are absolutely unequivocal."
Ginsberg added another potential caveat that "you might have to sell your house to get a PSCK9 inhibitor!" On this point, Nissen was sympathetic. "The biggest hurdle now in getting people on PSCK9 inhibitors is the pharmacy benefit managers."
What About Treatment of Type 2 Diabetes in Teenagers, and the Very Old?
An audience member wondered about the treatment of teenagers with type 2 diabetes, and whether there is an LDL goal for this patient group, or as Ginsberg described the dilemma, "Do you take a 15 year old [with diabetes] and put them on a statin, aspirin, and ACE inhibitor?"
The problem is "we have no studies on this, so it's hard to know," he observed. "Are they going to get coronary disease at age 30 because they have had type 2 diabetes for 15 years?"
Nissen said that he believes "a modestly low LDL over a lifetime will bring an enormous reduction in cardiovascular morbidity and mortality. It's probably the area under the LDL curve that counts, so if you start young, you might not have to go very low."
The two physicians also discussed the treatment of the over 75s, noting that guidance, and a recent article in the media, has suggested that people should stop taking statins once they reach this milestone.
Ginsberg said his patients had been asking him about this. "I tell them, 'If you don't get hit by a truck, or get cancer, you could live until 95. Why would you want to come off your statin?"
Nissen agreed wholeheartedly. "When I see a healthy 76, 77, and 78 year old, I want to prevent cardiovascular disease, so I ignore the guidelines. I don't think they are any different to a 74 year old."
"I think we have to come together — cardiologists and endocrinologists — and say that patients with diabetes need to get their LDL levels down. There is compelling evidence that getting people to low LDL levels is beneficial," he stressed, emphasizing that cardiovascular disease is the biggest killer of those with diabetes."