A 2013 front page New York Times article by Gina Kolata on PCSK9 inhibitors was inaccurate. Here is Kolata’ lede:
She was a 32-year-old aerobics instructor from a Dallas suburb — healthy, college educated, with two young children. Nothing out of the ordinary, except one thing.
Her cholesterol was astoundingly low. Her low-density lipoprotein, or LDL, the form that promotes heart disease, was 14, a level unheard-of in healthy adults, whose normal level is over 100.
The reason was a rare gene mutation she had inherited from both her mother and her father. Only one other person, a young, healthy Zimbabwean woman whose LDL cholesterol was 15, has ever been found with the same double dose of the mutation.
Here is an excerpt from the FDA clinical review of Sanofi/Regeneron’s PCSK9 inhibitor alirocumab:
We are aware of three cases of individuals homozygous (or compound heterozygous) for loss-of-function PCSK9 alleles with very low LDL-C concentrations that have been reported in the literature:
1. a 21-year-old African woman with an LDL-C of 15 mg/dL; no further information about this patient was provided, except that she was identified for genotyping at a postnatal clinic,
2. a 32-year-old African American woman with an LDL-C of 14 mg/dL; she is an apparently healthy, normotensive, fertile, college-educated individual with normal liver and renal function tests, and
3. a 49-year-old French white man who was found to have extremely low LDL-C (7 mg/dL) on admission for rapid-onset of an insulin-requiring diabetes mellitus of unknown etiology; LDL-C not during acute illness was reported to be 16 mg/dL. This patient was shown to have moderate liver steatosis on abdominal ultrasound with normal hepatic enzymes and liver function tests. He had no reported history of diarrhea, eye, or neurological abnormalities related to any vitamin deficiency. His mother was deceased at age 66 from dementia, whereas his father was healthy at age 79. His grandparents died at the ages of 79, 87, 91, and 94 years.
At this time there are too few cases to provide conclusive data about loss-of-function PCSK9 polymorphisms and the risk of human disease, although given the association of statins with diabetes risk, the development of diabetes in the 49-year-old man discussed above is of interest. (See Dr. Roberts’ safety review for further discussion of alirocumab and glycemic parameters).
The third case is the one missed by Kolata. It was published in Arteriosclerosis, Thrombosis, and Vascular Biology, an American Heart Association journal, in 2009, and could have been found with a PubMed search. The case is interesting in that it conflicts with one of the oft-repeated but inaccurate narratives with respect to PCSK9 inhibitors, the idea that all known persons with extremely low LDL due to having two PCSK9 loss-of-function mutations are completely healthy. I agree with the FDA reviewer that there are too few such cases to provide conclusive data about loss-of-function PCSK9 polymorphisms that result in extremely low LDL levels and the risk of disease. (The issue of whether alirocumab increases blood glucose and the risk of developing diabetes is also discussed extensively in the review, with the reviewer concluding that the evidence is inconclusive at this point.)
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 America. Gary 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.