Statins Linked to Diabetes and Cataracts

dr_duane_graveline_m.d._134By Duane Graveline, MD, MPH

In February 2012 the FDA belatedly announced that the use of statin drugs was causing diabetes. Although no precise figures were given for just how great an effect this was, several recent studies have given incidence figures for new onset diabetes ranging from 5% to 12 %.

I personally favor the higher figure because of the work done years ago by Siddals and his team that warned us to get ready because statin-associated diabetes was coming. I don't blame my colleagues for missing the significance of this title. Please bear with me on the following: Abrogation of insulin-like growth factor-1 (IGF-1) and insulin action by mevalonic acid depletion: synergy between protein prenylation and receptor glycosylation pathways. J. Biol Chem 279(37) 2004 by Siddals KW and others.

Their summary is just as challenging. You are not expected to understand this and you can skip this paragraph if you find it hard going. "The vasculoprotective effects of hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors (statins) correlate with cholesterol lowering. HMG-CoA reductase inhibitors also disrupt cellular processes by the depletion of isoprenoids and dolichol. Insulin and insulin-like growth factor (IGF) signaling appear particularly prone to such disruption as intracellular receptor processing requires dolichol for correct N-glycosylation, whereas downstream signaling through Ras requires the appropriate prenylation (farnesol). We determined how HMG-CoA reductase inhibition affected the mitogenic effects of IGF-I and metabolic actions of insulin in 3T3-L1 cells and examined the respective roles of receptor glycosylation and Ras prenylation. IGF-I- and insulin-induced proliferation was significantly reduced by all statins tested."

I must remind you that this came at a time when statins were first being marketed and very few doctors associated the effect of statins on anything in our bodies other than cholesterol. These researchers were talking of dolichols and isoprenes and glycosylation.

It is no wonder that few, if any, heard these warning of statin problems to come. No one at that time knew that to inhibit cholesterol synthesis through the use of statins also would inhibit dolichols and isoprenes and glycosylation because the same mevalonate pathway was involved.

Even though I was a clinician all of my working life and later, thoroughly dedicated to revealing to doctors and their patients the adverse effects of statin use, translation of these words of Siddals was not easy.

From the title through the abstract it illustrates the broad gap between the world of the medical researcher and that of the doctor who actually sees and treats people. All he said is that statin drugs designed to impair the synthesis of cholesterol must at the same time also inhibit the synthesis of dolichols and other factors involved in the very important task of glycosylation such as insulin manufacture.

This research team is predicting this in 2007. Four years earlier I had published my first book on statin side effects that included this. FDA was not to warn doctors until February 2012. I can understand FDA overlooking my book but I am perplexed that FDA should disregard something as critical to patient care as this work by Siddals.

Now we have general agreement among the medical community that 5 to 10% of everyone placed on a statin will get diabetes.

Diabetes is a major contributor to microvascular disease. That means it is a major contributor to such clinical entities as heart attacks, strokes, blindness and kidney failure, yet FDA is asking us to continue the use of statins unchanged because it does help to prevent heart attacks (while at the same time causing them). This is a tough sell to any thinking human being and it sort of makes me happy to be retired.

Statins also work to produce diabetes by another concurrent mechanism, that of progressive mitochondrial DNA damage. This is all secondary to what I mentioned at the very beginning of this article-the effect of statins on dolichols and glycoslylation. This effect underlies nearly all the serious statin associated problems from myopathy and neuropathy to hepatitis and diabetes.

The magic of dolichols and the glycosylation process take place in the endoplasmic reticulum in all of our cells. The great variation of biologic properties that sugars offer to proteins as the peptide strands are being assembled is the strength of diversity, with virtually unlimited combinations of attachments thereby possible.

Molecular biologists have calculated that four amino acids alone can produce 24 different structural combinations of the resulting peptide strand, but with the addition of just four biologically active sugars with their multiple points of attachments there can result in 124,000 possible structural combinations of the resulting glycoprotein strand.

This incredible specificity of design is a major strength of sugars with each variation of structure allowing a functional change. Just think of what we have accomplished in cellular function, all dependent on subtle variations of molecular structure. The end result of breakdown in these primary functions is failure of insulin production, loss of mitochonndrial energy for pancreatic function and even deterioration of pancreatic cell structure.

And now I want to direct your attention to the subject of cataracts.·

In an analysis of cataract prevalence among patients with and without diabetes taking statins, Machan and colleagues found that the prevalence of cataract increased at a faster rate in patients with diabetes who used statins. "Similar prevalence levels were seen in patients with diabetes who did not use statins and in patients without diabetes who did use statins," according to the researchers. "The prevalence of cataract increased at the slowest rate in patients without diabetes who did not use statins." The bottom line of this study is that diabetes increases cataract risk and statins increase both diabetes and cataract risk.

We are not talking just small amounts. A diagnosis of diabetes was also associated with an 84% greater risk of nuclear sclerosis, a 38% higher risk of cortical cataract, and a 52% rise in posterior subcapsular cataract. Statin use alone was associated with a 48% higher risk of nuclear sclerosis and a 48% rise in posterior subcapsular cataract. Diabetes was associated with an 82 percent increase in cataract risk and statin use with a 57 percent increase. According to the authors the two risk factors appeared independent of each other.

This new study strongly suggests that, just as we see in animals, cataracts in humans may be linked to the use of statin drugs. Although the mechanism has not as yet been defined it deserves to be mentioned that statin-associated dolichol mediated glycosylation defects are increasingly being identified as causative in a variety of biologic systems.

Waterloo Eye Study: data abstraction and population representation.

Age-related cataract is associated with type 2 diabetes and statin use.

Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor

May 2013


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