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Do PCSK9 inhibitors affect diabetes risk?

Two PCSK9 inhibitors, evolocumab and alirocumab, are under consideration at the FDA and will be the subject of advisory committee meetings on June 9 and 10. Evolocumab and alirocumab are monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme that plays a role in regulating levels of LDL cholesterol by binding to LDL receptors and promoting their degradation; the resulting reduction in LDL receptors reduces the liver’s ability to remove circulating LDL. PCSK9 inhibitors prevent PCSK9 from degrading LDL receptors; the increased LDL receptor density results in increased clearance of LDL from the bloodstream. The expectation is that lower LDL levels in patients who receive PCSK9 inhibitors will result in a reduction in cardiovascular events and this strategy is currently being tested in large outcomes trials, which will be completed in a few years. Until those trials are completed, the safety and efficacy of these drugs will not be known.

One of the unknowns with PCSK9 inhibitors is their effect (if any) on blood glucose levels and the development of new-onset diabetes. Statins are known to increase the risk of new-onset diabetes by about 9% overall, with increased risk from intensive vs. moderate intensity statin therapy. One reason to wonder whether PCSK9 inhibitors might have a similar effect is that both statins and PCSK9 inhibitors, though having different mechanisms of action, both involve the removal of LDL through upregulation of LDL receptors. The reason statins increase blood glucose is unknown, but recently it has been suggested that that the LDL receptor might be involved, with greater LDL receptor activity correlating with a higher risk of diabetes. A recent study showed that patients with familial hypercholesterolemia (FH) in the Dutch FH registry have a lower prevalence of type 2 diabetes as compared to their unaffected relatives. FH is a genetic disease in which the LDL receptor function is reduced, leading to higher serum levels of LDL cholesterol. In addition, the study found a dose-response relationship, with more severe FH mutations linked to lower risk of diabetes as compared to less severe mutations. In other words, the study showed an association between less functional LDL receptors and a lower prevalence of type 2 diabetes. In an editorial, David Preiss and Naveed Sattar note that the study suggests that “the expression and function of LDL receptors may be important for glucose homeostasis” and that the advent of PCSK9 inhibitors provides an opportunity to further examine a possible link between LDL receptor expression and glycemia and diabetes risk.

I’ve looked at some of the published data on PCSK9 inhibitors and blood glucose and diabetes risk. With respect to alirocumab, I abstracted a subset of the data in an abstract presented at the March 2015 American College of Cardiology conference.

As you can see, the data show small numerical increases in new-onset diabetes and worsening of preexisting diabetes, as well as larger increases in fasting glucose and hemoglobin A1c over the course of a year in patients on alirocumab as compared to patients on placebo (all patients were also on a statin). With respect to evolocumab, I found the following data:

1. A 52-week placebo-controlled trial of evolocumab in patients with hyperlipidemia published in the New England Journal of Medicine in 2014 found the mean change from baseline for fasting glucose at week 52 was 1.3 mg per deciliter for evolocumab and 0.4 mg per deciliter for placebo. The mean change from baseline for HbA1c at week 52 was 0.02% for evolocumab and 0.00% for placebo (table 3 and supplementary table S3).

1. The Osler trials recently published in the New England Journal of Medicine showed that 1.1% of the patients who received evolocumab developed diabetes, as compared to 0.7% of the patients in the standard of care group.

What do all these small differences add up to? It’s not possible to say yet, but I assume someone will do a meta-analysis at some point, and there may be some discussion of this issue in the FDA review of these agents, which will be posted prior to advisory committee meetings.

I should note that even if PCSK9 inhibitors do increase blood glucose and the risk of developing diabetes, they would still be very worthwhile for patients who are at significant risk of heart attack and stroke, if they are shown to be effective and have acceptable safety.

Alzheimer’s disease, familial hypercholesterolemia, and clinical trials

Welcome Jesse Ballenger to the blogosphere.  Jesse is a historian who specializes in the history of medicine and is the author of Self, Senility and Alzheimer’s Disease in Modern AmericaGary Schwitzer alerted me to Jesse’s post on Gina Kolata’s recent Sunday New York Times piece, How Do You Live Knowing You Might Have an Alzheimer’s Gene?, as well as to the existence of his blog, To Conquer Confusion:  A Historian’s Perspective on the Science and Experience of Alzheimer’s Disease and Dementia.  Jesse has both praise and criticism for Kolata’s story, and his post brings needed perspective on the history of research on Alzheimer’s as well as on the choice on Kolata’s part to present only the very optimistic views of certain Alzheimer’s researchers who “say that within a decade there could be a drug that staves off brain destruction and death.”  I agree with him that “Kolata should have raised questions about this claim, and talked to experts not directly involved in the research who are far less optimistic about its potential to so quickly lead to effective treatments.”  So please go read his post.

Kolata describes an American family in which many members are afflicted with early-onset Alzheimer’s caused by an autosomal dominant mutation.  Because the mutation is dominant, each affected family member has a 50% chance of passing the mutation on to each of his or her chidren.  The story is tragic and brought to my mind the emotions I experienced in 2001, when my daughter was diagnosed with heterozygous familial hypercholesterolemia (heFH) at age 8.  This is a genetic disease that causes very high LDL-cholesterol from birth and if untreated leads to early heart disease in a high percentage of patients.  At the time, I was only vaguely aware that there was a history of heart disease in my husband’s family and that his mother had had a heart attack.  At the urging of my daughter’s cardiologist, we asked my husband’s mother for more details and learned that her father had died of a heart attack at 35 and her brother, her only sibling, died of a heart attack at 40.  My mother-in-law suffered her first heart attack at age 58.  My husband inherited the mutation but has only a mild case, and my mother-in-law had never been told anything other than that she had high cholesterol, so my daughter’s diagnosis was the first occasion anyone in the family realized that the family history of early heart attacks was caused by a mutation.  Fortunately, unlike the case of Alzheimer’s disease, the risk associated with heFH can now be greatly reduced if patients are treated from an early age with a statin.  Homozygous FH patients, who have two copies of an FH mutation, are not so lucky and usually must undergo LDL apheresis on a regular basis.

Back to Kolata’s article:  I want to expand a little on a comment I wrote on Jesse’s post.  My comment related to Kolata’s comparison between the development of statins and the development of drugs to prevent Alzheimer’s.  As described in Kolata’s article, certain drugs in development are being tested in persons who are carriers of an Alzheimer’s mutation but have not yet developed symptoms of the disease.  The patients will receive one of several drugs or a placebo, and will be monitored for the development of certain biomarkers and, importantly, for the development of memory problems.  Kolata states that “Statins, the drugs that are broadly prescribed to block the body’s cholesterol synthesis, were first found effective in studies of people who inherited a rare gene that led to severe and early heart disease.”

The disease Kolata is presumably referring to is FH, but whether her statement is accurate depends on how one defines “effective.”  Early in the development of statins, after they had been tested in animals, they were given to a few patients with homozygous FH and heterozygous FH, as described in this 1992 article in the Journal of Lipid Research.  However, at that time the drugs were only being tested for their ability to lower LDL and for safety.  LDL-lowering is a surrogate endpoint.  If by “effective” one means the prevention of heart attacks and other cardiovascular events, the statement is inaccurate. When statins came on the market in the late 1980s, FH patients were excluded from the clinical trials that were conducted to show than statins not only lowered LDL but also prevented heart attacks, strokes and death. It was considered unethical to give an FH patient a placebo. To this day, no randomized controlled trial of statins with clinical endpoints has been done in FH patients and it is unlikely that one will ever be done. 

Direct evidence of the effectiveness of statins in heFH includes two observational studies, one of patients in a British registry and one of patients in a Dutch registry.  In addition, the ASAP trial compared a high dose statin with a moderate dose statin in heFH patients, but the endpoint was carotid intima media thickness, “IMT” (i.e., thickness of the carotid artery measured by ultrasound).  There was also a trial of statin vs. placebo in teenage FH patients using IMT as an endpoint.  In addition, many trials of statins have shown a benefit in non-FH patients with elevated LDL and it is reasonable to assume that this benefit would carry over to FH patients.

Thus, the comparison between the trials of investigational Alzheimer’s drugs in mutation carriers and the testing of statins in FH patients is not particularly apt.  The Alzheimer’s trials in patients with hereditary Alzheimer’s will be measuring the development of clinical symptoms of Alzheimer’s (i.e., memory loss, confusion, etc.).  The tests of statins in FH patients looked only at the effect of the drug on a surrogate endpoint (i.e., LDL-lowering) and no trials with clinical endpoints (i.e., heart attacks and other cardiovascular events and death) were done in FH patients.


Endo A.  The discovery and development of HMG-CoA reductase inhibitors. J. Lipid Res. 1992 33:(11) 1569-82. 

Neil A, Cooper J, Betteridge J, et al. Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. Eur Heart J 2008; 29: 2625-2633.

Versmissen J, Oosterveer DM, Yazdanpanah M, et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ 2008; 337: a2423.
Sijbrands E.  Inhibition of PCSK9 in Familial Hypercholesteolemia.  The Lancet, Early Online Publication, 26 May 2012.

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