Are PCSK9 Inhibitors for LDL Cholesterol Safe and Effective?

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Those with genetic mutations that leave them with an LDL cholesterol of 30 live exceptionally long lives. Can we duplicate that effect with drugs?

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Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.

Extrapolating down the graphs from large cholesterol-lowering trials using statin drugs suggests that the incidence of cardiovascular events like heart attacks would approach zero if the LDL cholesterol can be forced down below 60 in preventing one’s first heart attack, and down around 30 mg/dl for those trying to prevent another one. But is lower actually better? And is it even safe to have cholesterol levels that low?

We didn’t know, until PCSK9 inhibitors were invented. If that word sounds vaguely familiar, it’s because that was the gene I profiled in the last video. It’s the one that got mutated to give people such low LDL. And indeed, that’s how Big Pharma came up with the idea of trying to instead cripple PCSK9 with drugs. After a heart attack, intensive LDL cholesterol-lowering beyond a target of 70 does seem to work better. There were fewer cardiovascular deaths, heart attacks, or strokes at an LDL less than 30, compared with 70 or higher. Even compared to less than 70. There is a consistent risk reduction, even when starting as low as an average of 63, and pushing LDL down to 21, remarkably, showed no offsetting adverse side effects.

Maybe that shouldn’t be so surprising, given that that’s about the level at which we start out life. And there’s another type of genetic mutation that leaves people with LDLs of about 30 their whole lives, and they are known to have an exceptionally long life expectancy. Then wait. Where did we get this idea that cholesterol could fall too low?

The often-repeated suggestion that cholesterol lowering can be dangerous through depletion of cell cholesterol is unsupported by evidence, and does not take into account the exquisite balancing mechanisms our body uses. After all, remember that’s how we evolved. Until recently, most of us used to be running around with LDLs of around 50; so, that’s like normal for the human species. The absence of proof that low or lowered cholesterol levels are somehow bad for you contrasts with the substantial evidence that cholesterol reduction prevents coronary artery disease, our #1 killer.

What about hormone production, though? Since the human body needs cholesterol for synthesis of steroid hormones—like adrenal hormones, sex hormones—there’s a concern that there wouldn’t be enough. You don’t know, though, until you put it to the test. For decades, we’ve known that women on cholesterol-lowering drugs don’t have a problem with estrogen production. Nor does cholesterol lowering affect adrenal gland function. Nor does it impair testicular function in terms of the production of testosterone. If anything, statin drugs improve erectile function in men, which is what you’d expect from cholesterol lowering. But you’ll notice these studies only looked at getting LDL down to 70 or below. What about really low LDL?

On PCSK9 inhibitors, you can get most people under an LDL of 40 and some under 15! And…no evidence of impairment of adrenal or ovarian or testicular hormone synthesis even in patients with LDL levels under 15. The risk of heart attacks falls down in a straight line as LDL gets lower and lower, even down below 10, for example, without apparent safety concerns, but that’s over the duration of exposure to these drugs. The longest follow-up to date is about six years, using multiple medications to drop LDL as low as possible. Now, we can take comfort in the fact that those with extreme PCSK9 mutations, leading to a lifelong reduction in levels of LDL-C to under 20 their whole lives, remain healthy and have healthy kids. Cholesterol-affecting mutations are in fact what cause the so-called longevity syndromes, but that doesn’t necessarily mean the drugs are safe. The bottom line is we should try to get our LDL cholesterol down as low as we can, but much longer follow-up data are necessary any time a new class of drugs is introduced. So, so far, so good, but we’re only a few years out. For example, we didn’t know statins increased diabetes risk until decades after they were approved and millions had been exposed And not to mention PCSK9 inhibitors cost about $14,000 a year.

Please consider volunteering to help out on the site.

Video production by Glass Entertainment

Motion graphics by Avo Media

Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.

Extrapolating down the graphs from large cholesterol-lowering trials using statin drugs suggests that the incidence of cardiovascular events like heart attacks would approach zero if the LDL cholesterol can be forced down below 60 in preventing one’s first heart attack, and down around 30 mg/dl for those trying to prevent another one. But is lower actually better? And is it even safe to have cholesterol levels that low?

We didn’t know, until PCSK9 inhibitors were invented. If that word sounds vaguely familiar, it’s because that was the gene I profiled in the last video. It’s the one that got mutated to give people such low LDL. And indeed, that’s how Big Pharma came up with the idea of trying to instead cripple PCSK9 with drugs. After a heart attack, intensive LDL cholesterol-lowering beyond a target of 70 does seem to work better. There were fewer cardiovascular deaths, heart attacks, or strokes at an LDL less than 30, compared with 70 or higher. Even compared to less than 70. There is a consistent risk reduction, even when starting as low as an average of 63, and pushing LDL down to 21, remarkably, showed no offsetting adverse side effects.

Maybe that shouldn’t be so surprising, given that that’s about the level at which we start out life. And there’s another type of genetic mutation that leaves people with LDLs of about 30 their whole lives, and they are known to have an exceptionally long life expectancy. Then wait. Where did we get this idea that cholesterol could fall too low?

The often-repeated suggestion that cholesterol lowering can be dangerous through depletion of cell cholesterol is unsupported by evidence, and does not take into account the exquisite balancing mechanisms our body uses. After all, remember that’s how we evolved. Until recently, most of us used to be running around with LDLs of around 50; so, that’s like normal for the human species. The absence of proof that low or lowered cholesterol levels are somehow bad for you contrasts with the substantial evidence that cholesterol reduction prevents coronary artery disease, our #1 killer.

What about hormone production, though? Since the human body needs cholesterol for synthesis of steroid hormones—like adrenal hormones, sex hormones—there’s a concern that there wouldn’t be enough. You don’t know, though, until you put it to the test. For decades, we’ve known that women on cholesterol-lowering drugs don’t have a problem with estrogen production. Nor does cholesterol lowering affect adrenal gland function. Nor does it impair testicular function in terms of the production of testosterone. If anything, statin drugs improve erectile function in men, which is what you’d expect from cholesterol lowering. But you’ll notice these studies only looked at getting LDL down to 70 or below. What about really low LDL?

On PCSK9 inhibitors, you can get most people under an LDL of 40 and some under 15! And…no evidence of impairment of adrenal or ovarian or testicular hormone synthesis even in patients with LDL levels under 15. The risk of heart attacks falls down in a straight line as LDL gets lower and lower, even down below 10, for example, without apparent safety concerns, but that’s over the duration of exposure to these drugs. The longest follow-up to date is about six years, using multiple medications to drop LDL as low as possible. Now, we can take comfort in the fact that those with extreme PCSK9 mutations, leading to a lifelong reduction in levels of LDL-C to under 20 their whole lives, remain healthy and have healthy kids. Cholesterol-affecting mutations are in fact what cause the so-called longevity syndromes, but that doesn’t necessarily mean the drugs are safe. The bottom line is we should try to get our LDL cholesterol down as low as we can, but much longer follow-up data are necessary any time a new class of drugs is introduced. So, so far, so good, but we’re only a few years out. For example, we didn’t know statins increased diabetes risk until decades after they were approved and millions had been exposed And not to mention PCSK9 inhibitors cost about $14,000 a year.

Please consider volunteering to help out on the site.

Video production by Glass Entertainment

Motion graphics by Avo Media

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