Familial hypercholesterolemia is an autosomal dominant disorder resulting in severe elevation of total and LDL cholesterol due to defective hepatic LDL receptor. Heterozygotes occur in about 1 of 500 people in the United States. In some populations, such as French Canadians, the incidence for heterozygotes may be increased. Many people with familial hypercholesterolemia experience recurrent cardiovascular events at a young age and eventually die, prematurely.

For many, aggressive combination pharmacotherapy is sufficient and effective. However, in those in whom medications are either ineffective or not tolerated, LDL apheresis is another option. LDL apheresis is FDA-approved for the management of patients with severe elevation of LDL cholesterol who have not responded to at least six months of dietary modification and maximum tolerated drug therapy consisting of a trial of at least two classes of lipid -lowering medications.

There are two groups of patients for which LDL apheresis is indicated:

• Patients with an LDL level >300 mg/dL.
• Patients with an LDL level between 200 mg/dL to 300 mg/dL with CV disease.

During LDL apheresis, the plasma is separated from whole blood, and LDL and other apolipoprotein B-containing particles are removed from the plasma. Then, the plasma and blood are recombined and returned back to the patient. The entire procedure takes approximately two to three hours to perform.

A single LDL apheresis treatment may lower LDL between 73% and 83%. Because patients have a genetic defect, however, treatment must be repeated indefinitely. In general, individuals with LDL levels starting at>300 mg/dL are treated once per week, while individuals with LDL levels starting at 200 mg/dL are usually treated once every two weeks. Patients should continue their diet and lipid-lowering medications after initiating LDL apheresis.

LDL apheresis has been shown to regress atherosclerotic plaque and decrease the frequency CV events. In one study, the rate for CV events, death and subsequent interventions were reduced by 72% after six years of LDL apheresis compared to management with medication alone. Besides lowering LDL, LDL apheresis also lowers triglycerides, very-low density lipoprotein (VLDL), apolipoprotein B, fibrinogen, lipoprotein A, C-reactive protein, lipoprotein-associated phospholipase A2, blood viscosity and other markers associated with increased CVD risk.

Adverse events are rare. Transient hypotension during the procedure is the most common adverse event. In clinical trials, hypotension occurred in <1% of all treatments. ACE inhibitors increase this risk, presumably mediated through bradykinins. Therefore, we switch all patients on angiotensin-converting enzyme inhibitors to angiotensin receptor blockers which do not have this effect. Other antihypertensive agents should be withheld for 24 hours before the procedure. Our own patients undergoing LDL apheresis have tolerated the procedure well without any ill effects.

One disadvantage, besides the requirement of two or three-hour treatments every two weeks, is that LDL apheresis is expensive. Severe hypercholesterolemia thathas failed to respond to usual therapy, however, can also be expensive when considering not only the literal expense of repeated procedures and revascularization, but also the personal cost in terms of recurrent events and premature death. For patients in whom it is indicated, LDL apheresis is medically necessary and covered by many insurance plans.

Unfortunately, there continues to be a misconception that familial hypercholesterolemia is rare and that LDL apheresis is available only at large academic medical centers. Because of this, many patients who could potentially benefit from such life-saving therapy are never offered the opportunity.

Mabuchi H. Am J Cardiol.1998;82:1489-1495.

Mehta PK. Current Treatment Options in Cardiovascular Medicine. 2009;11:279-288.

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(With lots of help from Betty Schulz and Michele Tatro whose dedication to patient care deserves recognition.)

The pace of research and development in diabetes care over the past decade or so has been almost mind numbing for both physician and patient:

• several new classes of oral and injectable drugs
• new insulin preparations and analogs
• pens instead of syringes and needles
• improved blood glucose monitors with capability to download data onto a computer
• ongoing improvement for insulin pumps
• dramatic improvement in continuing glucose monitoring systems, increasingly capable of “talking” to the pump.

As physicians, we are in a much better position to tailor the therapy for individual patients than we have ever been, but that only applies to patients who have reasonable health care coverage and an ongoing income stream. Those less fortunate cannot, at least for now, take advantage of these opportunities.

I should quickly add that insulin via syringe and needle are of course as effective as pens (which are about twice as expensive) and several insulin options are available in both forms. The situation with newer oral agents is quite different with only sulfonylureas and biguanides available as generic preparations.

Glucose meters are inexpensive – at my local pharmacy the rebate offer is sometimes more than the cost of the meter – and do not need replacement very often. Test strips and lancets are recurring expenses and carry a significant economic burden.

The solution for those with type 2 diabetes is diet and lifestyle modification, which has been repeatedly demonstrated to be the most effective first step in diabetes management. This should be a mainstay of ongoing care for all our patients, but we all see patients who don’t follow this advice when they think they can take care of the diabetes with the drugs we prescribe.

Here’s where we both run into trouble. Depression and diabetes are common bed-fellows even in good times, but the jolt from losing your job and health care benefits either aggravates an underlying depression or creates a reactive depression. Add to that a Michigan winter (although we have had a much easier winter this year than those in the Northeast) and seasonal affective disorder and it becomes increasingly more difficult to give diabetes and other health care issues the same attention as they did when employed. As of the end of January, Michigan still led the nation in unemployment rates, but there were many states not far behind and the national average was about 10%.

Education about diet is also essential, but adherence is difficult if the patient doesn’t have the wherewithal to afford quality meals. I have previously blogged about the importance of a good night's sleep – evaluate for sleep apnea – and checking testosterone levels in men so that there is the energy needed for the exercise part of diet and exercise. Most of us don’t have the skills or equipment needed to properly check for diabetic retinopathy, so regular visits to an ophthalmologist has to continue. Checking for peripheral neuropathy and peripheral vascular disease belongs to us so we can stave-off regular visits to the appropriate specialists. Then what?

In our practice we are trying, with very limited success, to get walking groups started as we head towards spring. We are posting this blog in the hope that those faced with a similar situation can give us some clues as to where to go from here.

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A 33-year-old woman with type 1 diabetes came to the clinic for help adjusting her insulin pump therapy. She had been on the insulin pump since shortly after her diagnosis was established 12 years earlier. She was a bright, articulate, middle-level executive in a major company and knew more about pump management than most of us, certainly more than me. She came to the clinic with her husband and their 13-month-old daughter and she had very comfortably managed her pump during pregnancy and the early hectic days of motherhood.

Earlier in the day she had seen her gastroenterologist, who had initiated therapy with prednisone (Vintage Pharms) 20 mg daily and azathioprine (Azasan, AAIPharma LLC) for treatment of autoimmune hepatitis. She has been forewarned of this regimen, which is why she had made the appointment with me, but was appropriately concerned about requiring frequent adjustments. She had been told that the azathioprine would be only a short course but that she should anticipate requiring prednisone for some time.

Together we designed changes to her insulin pump settings, made arrangements for continuous glucose monitoring (CGM) for three days, and set things in motion for her to purchase her own CGM.

When we had that all settled, she wanted to know how therapy for hepatitis would affect the treatment of her thyroid disease. The physical exam suggested she was euthyroid on her current replacement dose but I did order a thyroid-stimulating hormone test to be sure since it which had not been measured for several months.

When the result came back the next day the TSH was reported as 155 mU/L!

Autoimmune thyroid disease is a fairly common finding in type 1 diabetes and usually easy to control but between baby, work and hepatitis she had paid less attention to her thyroid medication – more often than not missing a dose. A repeat physical exam was unchanged, even knowing how hypothyroid she was and I am still struggling to explain this other than a suboptimal exam by me.

The prednisone is going to increase her insulin requirements and likely have some positive effect on the hypothyroidism (albeit not standard therapy for that). However, while she is recovering a euthyroid state her metabolic rate will be in a state of flux and glycemic control will be hard to stabilize.

The good news is that she was stunned by the TSH, has a very supportive husband and has taken a medical leave from work (working from home at her own pace with great understanding from her company) to devote the time necessary to care for herself and baby.

Three months into therapy for hepatitis she is off the azathioprine, her TSH is normal and she has had no symptomatic hypoglycemic events. Her CGM data are not so clean and it is an ongoing struggle to handle the diabetes, the prednisone and the effects of prednisone on her weight and appearance.

Now it is time to think about the skeletal effects of steroid therapy, so easily overlooked in someone with all that my patient has going on. With type 1 diabetes she is likely to have lower bone mineral density when compared with her peers, temporarily aggravated by pregnancy and lactation (bone loss during pregnancy and lactation is not trivial but is almost completely recoverable under normal circumstances). She does not really need to have a BMD test since it would not influence my intervention decision, but the insurance would not cover her therapy on the basis of history alone – sometimes they refuse coverage without a BMD even when the history includes an osteoporosis related minimal trauma fracture. Of the several options available, I selected IV ibandronate (Boniva, Roche) every three months, given as a short IV push since she is already scheduling visits to one doctor or another that frequently.

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