New cholesterol guidelines: Worth the wait?

GROUP 3: DIABETES, AGE 40–75, LDL-C 70–189, NO CLINICAL ASCVD

Advantages of the new guidelines

• They call for aggressive treatment of people with diabetes, a group at high risk that derives significant benefit from statin therapy, as shown in randomized controlled trials.

Limitations of the new guidelines

• Although high-intensity statin therapy is indicated for this group, we believe that, using the new risk calculator, some patients may receive overly aggressive treatment, thus increasing the possibility of statin side effects.
• The guidelines do not address patients younger than 40 or older than 75.
• Diabetic patients have a high residual risk of ASCVD events, even on statin therapy. Yet the guidelines ignore the potential benefits of more aggressive LDL-lowering or non-LDL secondary targets for therapy.

Case 2: How low is too low?

A 63-year-old white woman, a nonsmoker with recently diagnosed diabetes, is seen by her primary care physician. She has hypertension, for which she takes lisinopril 5 mg daily. Her fasting lipid values are:

• Total cholesterol 160 mg/dL
• HDL-C 64 mg/dL
• Triglycerides 100 mg/dL
• Calculated LDL-C 76 mg/dL.

Her systolic blood pressure is 129 mm Hg, and based on the new risk calculator, her 10-year risk of cardiovascular disease is 10.2%. According to the new guidelines, she should be started on high-intensity statin treatment (Table 1).

Although this is an acceptable initial course of action, it necessitates close vigilance, since it may actually drive her LDL-C level too low. Randomized controlled trials have typically used an LDL-C concentration of less than or equal to 25 mg/dL as the safety cutoff. With a typical LDL-C reduction of at least 50% on high-intensity statins, our patient’s expected LDL-C level will likely be in the low 30s. We believe this would be a good outcome, provided that she tolerates the medication without adverse effects. However, responses to statins vary from patient to patient.

High-intensity statin therapy may not be necessary to reduce risk adequately in all patients who have diabetes without preexisting vascular disease. The Collaborative Atorvastatin Diabetes Study¹² compared atorvastatin 10 mg vs placebo in people with type 2 diabetes, age 40 to 75, who had one or more cardiovascular risk factors but no signs or symptoms of preexisting ASCVD and who had only average or below-average cholesterol levels—precisely like this patient. The trial was terminated early because of a clear benefit (a 37% reduction in the composite end point of major adverse cardiovascular events) in the intervention group. For our patient, we believe an alternative and acceptable approach would be to begin moderate-intensity statin therapy (eg, with atorvastatin 10 mg) (Table 1).

Alternatively, in a patient with diabetes and previous atherosclerotic vascular disease or with a high 10-year risk and high LDL-C, limiting treatment to high-intensity statin therapy by itself may deny them the potential benefits of combination therapies and targeting to lower LDL-C levels or non-HDL-C secondary targets. Guidelines from the American Diabetes Association²⁸ and the American Association of Clinical Endocrinologists²⁹ continue to recommend an LDL-C goal of less than 70 mg/dL in patients at high risk, a non-HDL-C less than 100 mg/dL, an apolipoprotein B less than 80 mg/dL, and an LDL particle number less than 1,000 nmol/L.

GROUP 4: AGE 40–75, LDL-C 70–189, NO ASCVD, BUT 10-YEAR RISK ≥ 7.5%

Advantages of the new guidelines

• They may reduce ASCVD events for patients at higher risk.
• The risk calculator is easy to use and focuses on global risk, ie, all forms of ASCVD.
• The guidelines promote discussion of risks and benefits between patients and providers.

Limitations of the new guidelines

• The new risk calculator is controversial (see below).
• There is potential for overtreatment, particularly in older patients.
• There is potential for undertreatment, particularly in patients with an elevated LDL-C but whose 10-year risk is less than 7.5% because they are young.
• The guidelines do not address patients younger than 40 or older than 75.
• They do not take into account some traditional risk factors, such as family history, and nontraditional risk factors such as C-reactive protein as measured by ultrasensitive assays, lipoprotein(a), and apolipoprotein B.

Risk calculator controversy

The new risk calculator has aroused strong opinions on both sides of the aisle.

Shortly after the new guidelines were released, cardiologists Dr. Paul Ridker and Dr. Nancy Cook from Brigham and Women’s Hospital in Boston published analyses³⁰ showing that the new risk calculator, which was based on older data from several large cohorts such as the Atherosclerosis Risk in Communities study,³¹ the Cardiovascular Health Study,³² the Coronary Artery Risk Development in Young Adults study,³³ and the Framingham Heart Study,^34,35 was inaccurate in other cohorts. Specifically, in more-recent cohorts (the Women’s Health Study,³⁶ Physicians’ Health Study,³⁷ and Women’s Health Initiative³⁸), the new calculator overestimates the 10-year risk of ASCVD by 75% to 150%.³⁰ Using the new calculator would make approximately 30 million more Americans eligible for statin treatment. The concern is that patients at lower risk would be treated and exposed to potential side effects of statin therapy.

In addition, the risk calculator relies heavily on age and sex and does not include other factors such as triglyceride level, family history, C-reactive protein, or lipoprotein(a). Importantly, and somewhat ironically given the otherwise absolute adherence to randomized controlled trial data for guideline development, the risk calculator has never been verified in prospective studies to adequately show that using it reduces ASCVD events.