Low 'LDL' Puts You At Risk For Cataract

According to a study in the Journal of the American College of Cardiology, very low levels of LDL, or bad cholesterol, puts you at a greater risk for cataract. The researchers studied patients with heart disease taking LDL inhibitors to achieve unusually low cholesterol level. There were no adverse effects noted from the inhibitors except for an increased risk of cataracts.

This is news and not good news. I have had cataracts and the operation to correct my vision, but I have not used a PCSK9 inhibitor.

The cholesterol-lowering drug, or statins, used in the study were specifically PCSK9 inhibitor, and no reports of side affects have surfaced, including memory impairment or nervous system disorders. However, the study showed that the risk for cataract is increased among statin users as compared with nonusers. According to the researchers, to glean the maximum amount of benefits and avoid risks, statin use specifically for primary prevention, should be carefully weighed.

According to the EurekAlert, statins are largely used to lower LDL cholesterol, or bad cholesterol. They are prescribed in hopes to lower risks of a heart attack or stroke. However, some high risk patients need to reduce their LDL level even further.

PCSK9 inhibitors can help them do that, but concerns on very low levels of LDL cholesterol effects on the body functions have risen. An analysis did show an increased incidence of cataracts in patients with LDL less than 25 compared to those greater than 25. This finding could be because reducing cholesterol accelerates underlying aging-related changes resulting to the development of cataracts.

According to The Jama Network, cataract development may be induced by oxidative stress, including a possible mitochondrial effect, which can potentially increase risk for cataract. Previous studies have seen increased rates of cataract among animals and humans with hereditary cholesterol deficiency. The recent studies on the effects of very low bad cholesterol have yielded an unexpected finding, putting patients who take statins in a precarious condition.

Please read this blog as it does add the side effect of type 2 diabetes, which is not recognized by this study.

PCSK9 Inhibitors Increase Diabetes Risk

I think Dr. Malcolm Kendrick will be happy to see this study. Back in July 2015, he predicted this would happen. The results of two independent studies of genetic variants suggest that treatment with a PCSK9 inhibitor could increase the riskfor diabetes.

In the first study, involving 112,772 participants, the researchers constructed two genetic scores consisting of PCSK9 and HMGCR variants to mimic the effects of treatment with PCSK9 inhibitors and statins, respectively. They found that low-density lipoprotein (LDL) cholesterol-lowering variants in both genes were associated with a reduction in the risk for cardiovascular events, but an elevated risk for diabetes.

After adjustment for a decrease in LDL cholesterol levels of 10 mg/dl, the team found a “nearly identical” reduction of 18.9% and 19.1% in the risk for cardiovascular events with the presence of PCSK9 and HMGCR variants, respectively.

These findings suggest that “treatment with a PCSK9 inhibitor should reduce the risk of cardiovascular events by approximately the same amount as treatment with a statin,” write study authors Brian Ference (Wayne State University School of Medicine, Detroit, Michigan, USA) and colleagues in The New England Journal of Medicine.

However, the presence of PCSK9 variants was associated with an 11.2% increase in the risk for diabetes per decrease of 10 mg/dl in LDL cholesterol, and the presence of HMGCR variants was associated with a 12.7% increase in risk.

“Like statins, PCSK9 inhibitors may also increase the risk of new-onset diabetes,” say the authors. However, because the proportional reduction in cardiovascular disease risk associated with PCSK9 variants was “much greater” than the increased risk for diabetes, they conclude that “as with statins, the reduction in cardiovascular risk with PCSK9 inhibitors should far exceed any potential increased risk of diabetes.”

In the second study, Amand Schmidt (University College London, UK) and colleagues analyzed data from 568,448 individuals included in randomized controlled trials, observational studies, and genetic consortia to estimate the association between PCSK9 variants and type 2 diabetes risk.

The team showed that four independent PCSK9 variants were associated with a reduction in LDL cholesterol levels, ranging from 0.02 mmol/L (0.78 mg/dl) to 0.34 mmol/L (13.15 mg/dl) per LDL cholesterol-reducing allele.

When the variants were combined into a weighted gene-centric score and scaled to a reduction in LDL cholesterol of 1 mmol/L (38.67 mg/dl), presence of the variants was associated with a 29% increased risk for type 2 diabetes.

The study authors also found that PCSK9 variants were associated with increased fasting glucose, body weight, and waist-to-hip ratio, but not with glycated hemoglobin, fasting insulin, or body mass index.

"Genetic variants in PCSK9 that associate with lower concentrations of LDL cholesterol are also associated with a modestly higher risk of type 2 diabetes and with associated differences in measures of glycemia,” write the authors in The Lancet Diabetes and Endocrinology.

They recommend that future trials of PCSK9 inhibitors should carefully monitor changes in metabolic markers, including body weight and glycemia, and conclude that genetic studies “could be more widely used to interrogate the safety and efficacy of novel drug targets.”

Patients, Beware of New Statin Push for PCSK9 Inhibitors

This and the next two blogs are about the newest statins in the PCSK9 class and put on limited use by the FDA.

Amgen and Sanofi/Regeneron, the makers of the two newly approved cholesterol drugs, evolocumab (Repatha) and alirocumab (Praluent), are fueling an explosion of new programs to identify large numbers of new patients who are candidates for the expensive drugs.

An example is a $120 million partnership between Regeneron and Geisinger Health System to broaden the search for genes and drug targets well beyond familial hypercholesterolemia, which is the main indication for PCSK9 inhibitors right now.

By comparing "genetic information against medical histories, Geisinger and Regeneron hope to eventually develop new means of diagnosing, preventing and/or treating medical conditions -- before they cause significant harm. Some participants may also receive information that could be useful in their own medical care."

Peter Berger, MD, who recently became the senior vice president of clinical research at the North Shore-Long Island Jewish Health Care System made comments about the two expensive drugs. Before that, he was at Geisinger, where he was involved in the Regeneron negotiations, though he emphasized that he was not speaking for Geisinger and he was not involved with the final deal. Berger said that at North Shore-LIJ, his main concern is to identify untreated patients who can benefit from treatment, patients who's LDL is way too high on a statin.

Berger then stated, "Most health care institutions, including my own, have too many patients with very high LDLs (for example, greater than 400 mg/dl untreated, or greater than 250 mg/dl on the maximal dose of a potent statin), and do a poor job of screening the family members of such patients."

While it may not matter to the patient what the actual cause of the high LDL is, all the medical people are concerned about at this point is whether they can earn money for getting these patients on the expensive drug. They will bypass any nutritional help and recommend the drug.

“Berger said he reached out to the companies to see if they would help explore the novel use of informatics to help identify such high-risk patients and get them to goal. He said he hopes to establish a program at North Shore-LIJ with industry support to identify such high-risk and insufficiently treated patients. Berger is keenly aware of the potential economic impact of the PCSK9 inhibitors and said that the study he is proposing contains an analysis of the economic impact of the drugs. In fact, he said that the drug companies readily agreed that such an analysis be a part of any study they fund.”

“Berger admitted, he was extremely concerned about the price of drugs in general, including the PCSK9 inhibitors. The pricing of drugs in this country is obscene. In the case of the PCSK9 inhibitors, I hope a third or a fourth PCSK9 inhibitor hits the market and drives the price down."

“But, he said, he's "not concerned at all that by identifying and screening more patients we will be expanding the pool for these drugs," as long as the patients receiving such therapy are appropriately selected." Berger emphasized that all such patients should be counseled about the role of diet and exercise, but did acknowledge, however, that intensive lipid lowering drug therapy is virtually always needed for patients with LDLs in the 400 range.”

All I would add to this is that as long as there is money flowing into his pocket, he will say and advocate for anything.