Conference Coverage

Aggressive lowering of LDL cholesterol: Is it a good idea?



– Powerful drugs now make it possible to lower LDL cholesterol levels to dramatically low levels. But is this a good idea? There are risks, and a cardiologist urged diabetes professionals to not overdo cholesterol reduction. But a colleague argued in favor of aggressively targeting “bad” cholesterol.

Dr. Steven Nissen Catherine Hackett

Dr. Steven Nissen

“We used to say you can’t be too rich or too thin. We now say you can’t be too rich or too thin or have a too-low LDL cholesterol,” said cardiologist Steven E. Nissen, MD, chairman of cardiovascular medicine at the Cleveland Clinic Foundation, who spoke at the annual scientific sessions of the American Diabetes Association about the wisdom of extreme LDL cholesterol lowering.

Dr. Nissen faced off in a debate with cardiologist Sanket Dhruva, MD, of the University of California, San Francisco, who doesn’t support aggressive LDL cholesterol lowering.

It is fine, Dr. Dhruva said, to treat patients so their LDL cholesterol levels drop below 100 mg/dL. “I don’t think there’s any argument there.”

But Dr. Dhruva questioned whether it’s a good idea to generally decrease LDL cholesterol well below 70 mg/dL, as is now possible with the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

Dr. Sanket Dhruva

He pointed to a 2010 study that found aggressively lowering LDL cholesterol led to a mean net gain of 4.1 quality-adjusted life-years in high-risk patients, but less than 1 quality-adjusted life-year in low-risk patients. According to him, the study also found that the biggest benefits in both high- and low-risk patients came from the initial lower statin dose (Arch Intern Med. 2010 Jun 28;170[12]:1037-44).

“It’s really the statin initiation that provides the most benefit to our patients with diabetes,” Dr. Dhruva said.

Also, he added, a 2016 study questioned the value of aggressively lowering LDL cholesterol. It found that, although patients on statins with LDL cholesterol levels of 70-100 mg/dL had a lower risk of adverse cardiac outcomes than did those with levels between 100 and 130 mg/dL, no additional benefit was gained by achieving an LDL cholesterol level below 70 mg/dL (JAMA Intern Med. 2016 Aug 1;176[8]:1105-13)

As for risks, Dr. Dhruva highlighted a 2016 pooled analysis of 14 trials that linked the PCSK9 inhibitor alirocumab (Praluent) and LDL cholesterol levels below 25 mg/dL to significantly higher levels of cataracts, compared with levels of at least 25 mg/dL (hazard ratio, 3.4).

There are other reasons to be cautious of aggressive LDL cholesterol lowering. For one, many patients are not on statins when they’re prescribed PCSK-9 inhibitors. “We’re sometimes missing the building blocks before getting to expensive medications,” he said.

He added that PCSK-9 inhibitors are pricey, and some patients can’t get access to them. “Lipid control is incredibly important, but what about the stress or anxiety of our patients who are told this medication will reduce their cardiac risk but they can’t afford it? That’s not good for their cardiovascular risk.”

For his part, Dr. Nissen challenged Dr. Dhruva’s concerns about the cost of the drugs. “It’s not like they’re way out of line in terms of expense,” he said, noting that their cost – several thousand dollars a year – is similar to the cost of diabetes drugs known as glucagonlike peptide–1 receptor agonists and sodium-glucose transporter 2 inhibitors.

According to Dr. Nissen, multiple studies have supported aggressive LDL cholesterol lowering. “You’re going to see this over and over again in clinical trials: Every time we lower LDL by more, we get more reductions in morbidity and mortality.”

For example, he said, the FOURIER trial of the PCSK9 inhibitor evolocumab (Repatha) found that it lowered LDL cholesterol levels to a median 30 mg/dL “and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets [N Engl J Med 2017;376:1713-22].”

Dr. Nissen pointed to another study, this one also from 2017, that reported “in individuals with 5-year risk of major vascular events lower than 10%, each 1 mmol/L reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1,000 over 5 years. This benefit greatly exceeds any known hazards of statin therapy.”

In regard to adverse effects, he said, research has hinted at a slight uptick in blood sugar levels “that does not take away the major cardiovascular benefits of the drugs.”

Overall, he said, “compelling evidence from trials in hundreds of thousands of patients demonstrates that reducing LDL cholesterol to very low levels reduces cardiovascular events in broad populations and is extremely safe.”

Dr. Nissen reported consulting for many pharmaceutical companies and performing clinical trials for Amgen, AbbVie, AstraZeneca, Cerenis Therapeutics, Esperion Therapeutics, Lilly, Novartis, Novo Nordisk, the Medicines Company, Orexigen Therapeutics, Takeda, and Pfizer. He does not receive income for honoraria, speaking fees, or consulting fees as they are paid directly to charity.

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