ENDO 2019: 101st Annual Meeting of the Endocrine Society:

Managing Complex Lipid Disorders: Choosing the Right Pharmacotherapy

With Robert H. Eckel, MD

With cardiovascular disease inserting itself into the clinical care of most endocrinology patients, having greater insights regarding challenging cases of hyperlipidemia will serve both the health practitioner and patient well.

Looking beyond usual efforts in managing hypercholesterolemia, Robert H. Eckel, MD, the Charles A. Boettcher II Endowed Chair in Atherosclerosis and director of the Lipid Clinic at the University of Colorado School of Medicine in Aurora, presented a session focused on  therapeutic advances in lipid therapy in difficult to treat patients,1 at ENDO 2019 in New Orleans, Louisiana.     

Choose the right cholesterol-reducing drug in a patient with severe hypertriglyceridemia. When patients don't respond to statin therapy, what is the next best medication to consider? Photo: 123rf

After the session, Dr. Eckel shared topline treatment strategies with EndocrineWeb regarding three types of challenging patients who have been known to present at the clinic, each requiring a different approach to pharmacotherapy for triglyceridemia.

Addressing Combined Hyperlipidemia in a Patient with a Statin Intolerance

Case 1 concerned a 69-year old woman who had combined hyperlipidemia, hypertension, prediabetes and had had a recent myocardial infarction. She had developed a statin intolerance after trialing four different statins both low- and high-intensity. Her inability to take this common lipid-lowering agent was well documented in her medical history. She was taking ezetimibe (10 mg/d) and omega-3 fatty acids (930 mg/bid).

“Ultimately, she came to my clinic with the following lab findings,” he said.

  • Total cholesterol: 254 mg/dL
  • Low density lipoprotein-cholesterol (LDL-C): 158 mg/dL.
  • Triglycerides (TG): 192 mg/d
  • High density lipoprotein-cholesterol (HDL-C): 58 mg/dL
  • Lipoprotein (a): 14 mg/dL
  • Hemoglobin (Hb) A1c: 5.8%
  • hs-C Reactive Protein (CRP); 1.8 mg/L

“In a patient such as this, the existing cholesterol-lowering guidelines do not offer a clear treatment path.  What is evident is that we have to treat her more aggressively to address the high LDL-C level,” said Dr. Eckel. 

Which of the following options might be considered?

1) Reevaluate her stain response

2) Colesevelam (1875 mg/bid);

3) Evolocumab (140 mg/biweekly);

4) Alirocumab (75 mg/biweekly)

“While in most instances the preferred approach for a patient with this clinical profile would be to initiate or adjust the statin, this option is unavailable to her, and she’s already taking ezetimibe, which has had only a modest LDL-lowering effect,” he said.

“Adding colesevelam may achieve a 20% reduction which wouldn’t be sufficient, so the decision was to treat her with a PCSK9 inhibitor (ie, evolocumab),” he said. “By making this choice, we might expect to achieve a reduction in LDL-C of about 60%, which will get her into a reasonable level at about 55 mg/dL.”

Best Treatment Approach for Hypertriglyceridemia with Type 2 Diabetes

In the second patient case, a 59-year-old, female non-smoker who presented with moderately severe hypertriglyceridemia. In addition, she had type 2 diabetes (T2D), her blood pressure was 135/80, her body mass index (BMI) was 32 kg/m2 , and she had experienced an MI a few years ago.

Her labs and lipid levels as reported were:

  • Total choleseterol: 240 mg/dL
  • TG: 511 mg
  • LDL-C: 101 mg
  • HDL-C: 39 mg/dL
  • Lipoprotein (a): 12 mg/dL
  • Apo B : 115 mg/dL
  • Fasting blood glucose (FBG): 104 mg/dL
  • HbA1c at 6.7%   

Thus, the discussion focused on the getting the patient to a goal TG under 200 mg/dL, and LDL-C under 100 mg/dL, and an Apo B of less than 80 mg/dL.

In these patients, in terms of identifying non-polar, lipophilic particles, the TG represent those particles that began as LDL-C in the liver but through the actions of lipoprotein lipase-mediated metabolism get broken down into smaller particles, or remnants, which ultimately generate LDL.

“In my opinion, triglycerides do not cause cardiovascular disease; rather, the remnants of VLDL and chylomicrons are atherogenic, and levels of the hepatic form of Apo B ApoB-100, reflect the number of VLDL and remnant particles,” Dr. Eckel told EndocrineWeb.

“This concept shouldn’t be our only focus but TG-lowering with a fibrate or omega-3 fatty acids should be our first priority, in general,” he said. “However, In this patient, an Apo B reduction from 115 to 90 mg/dL may be sufficient to reduce her CVD risk by up to 20-30%."

“Considering the strong correlation between non-HDL-C and Apo B, the 95th percentile confidence intervals for any given level of non-HDL-C for Apo B is a 2-fold difference in Apo B. Thus, if the Apo B is not at goal, the best pharmacotherapeutic approach to lowering Apo B is to add 10 mg of ezetimibe to a moderate- or high-intensity statin and fibrate or omega-3 fatty acids,” said Dr. Eckel.  

“This approach offers a very practical way to assess patients with hypertriglyceridemia in terms of how they may actually gain cardiovascular benefits from lipid-lowering drugs. Unfortunately, there isn’t the evidence yet to support this approach yet, but I’m hopeful that at some point, we will have the data to look at this scenario more closely with regard to lowering Apo  rather than just focusing on reducing TG.”

Treating A Common Triad: Type 2 Diabetes, Coronary Heart Disease, and Triglyceridemia

A 45-year-old man came to the clinic to address severely elevated plasma triglycerides. He had a diagnosis of coronary heart disease for which he had had multiple angioplasties (percutaneous coronary interventions), with poorly controlled T2D and hypertension for more than 20 years.1

Five months earlier, he had been hospitalized for chest pain but a cardiac event was ruled out; labs of note at the time: TG at 2509 mg/dL and HbA1c of 10.2%

He was discharged home with instructions to follow a low-fat diet and escalated dosing of insulin glargine beginning at 10 units daily. His medications upon presenting at the clinic included: glargine (70 units), rosuvastatin (20 mg), clopidogrel (75 mg), aspirin (81 mg), and twice daily—metformin (1 g), glipizide (10 mg), gemfibrozil (600 mg bid), and omega 3 FAs (1.6 g). He had a BMI of 30.8 kg/m2 and  blood pressure of 138/76.

His labs were:

  • Total cholesterol: 259 mg/dL
  • TGs: 1965 mg/dL
  • HDL-C: 35 mg/dL
  • HbA1c: 7.8%
  • TSH: 1.6 mIU/L

“Defining this patient’s type of hyperlipidemia—severe elevated triglycerides—remains under debate but, in general, it is considered that a TG level above 500 mg for which the Food and Drug Administration granted approval for omega 3 fatty acid as useful in reducing the risk for pancreatitis.3

In evaluating a patient with triglycerides over 1,000 mg/dL, most of these patients have reached a TG level where their removal from the plasma is saturated,4  which is condition that Dr. Eckel likened to a sink that empties nicely when water is poured into it during normal function but when the sink becomes full, (if the water was instead plasma TG, then the water (or TG) is not adequately cleared and so overflows to the floor.  

“What is needed here is to reduce plasma TG where triglyceride clearance is not saturated to allow fibrates and/or omega-3 FAs to work. To achieve this, the strategy is to reduce saturated fat to less than 5% of calories. In general, a ~25% drop in TG daily can be expected,” said Dr. Eckel. "Because the medications cannot work when the plasma TG level is much above 1,000 mg/dL, I think it is best to stop all meds as they are clearly not working. This is something we should consider more often,”5 he said.

“In this particular circumstance, the patient is likely to be frustrated and the physician unsatisfied because despite giving these medications, the patient remains severely hypertriglyceridemic. As such, there is a good case for stopping all pharmacotherapy, at least briefly,” said Dr. Eckel. 

“This is important because severe hypertriglyceridemia may result in pancreatitis, which is an outcome that we certainly want to avoid,” he said. Acute pancreatitis can be fatal in up to 5% of patients.

If the TG level does not fall below 1,000 mg/dL, the patient should be hospitalized to institute a more controlled diet.” he said.  

Dr. Eckel provided an overview of his presentation following the session for EndocrineWeb:

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