Monitoring Therapeutic Response

Introduction

This section covers monitoring therapeutic response, adherence and tolerability. Successful cardiovascular (CV) prevention efforts are supported by an ongoing therapeutic relationship between the patient, their support system and healthcare providers. Randomized trials of statin therapy had excellent drug adherence and patient retention, which contributed to the large relative reductions in the risk of CV events. Study participants were also closely monitored for adverse events. The 2018 multi-society cholesterol guideline panel used this evidence base to develop recommendations for regular clinic visits to monitor adherence and response to drug and lifestyle therapy and to assess adverse events.

Regular Clinic Visits

Adherence and response to therapy, which includes a fasting lipid panel and safety indicators should be assessed within 4 to 12 weeks of initiating a statin, or a change in therapy and regularly thereafter. Follow-up visits should be performed every 3 to 12 months once adherence to lifestyle and drug therapy has been established.

Evaluating Safety

Liver—Based on the excellent record of hepatic safety in the statin randomized controlled trials (RCTs), there is no longer a need to routinely monitor liver function tests if levels are normal before starting therapy unless symptoms of hepatitis occur. The Food and Drug Administration (FDA) concurs, with no evidence of long-term hepatic adverse effects for statins. Management of liver function test abnormalities in statin-treated patients is discussed in Managing Adverse Effects During Statin Therapy.

Muscle— CK levels should only be measured if the patient has muscle symptoms that are very severe or in the presence of objective muscle weakness. Management of muscle symptoms in statin-treated patients is discussed in Managing Adverse Effects During Statin Therapy.

Diabetes— Statins modestly increase the risk of diabetes mellitus in individuals already at risk for diabetes mellitus, thus screening for diabetes should be done according to regular diabetes screening guidelines.

Evaluating Therapeutic Response

In accordance with expected therapeutic responses, the 2018 multi-society guideline suggests specific low-density lipoprotein cholesterol (LDL-C) percent reduction (instead of absolute target) objectives for statin treatment. To reach the target average LDL-C decrease, options include intensification of lifestyle or statin therapy, or adding a nonstatin to the maximally tolerated statin therapy.

Anticipated Therapeutic Response

• High-intensity statin—the anticipated therapeutic response for a high-intensity statin is on average a ≥50% reduction in LDL-C from baseline (when the baseline LDL-C is unknown, it was observed that LDL-C <100 mg/dL was achieved in the high-intensity statin trials).
• Moderate-intensity statin—a 30% to <50% reduction from baseline would be expected on average for a moderate-intensity statin.
• Ezetimibe—when added to statin therapy, ezetimibe provides an additional 15% to 25% reduction in LDL-C.
• Alirocumab—alirocumab reduces LDL-C by 43% to 58% in combination with statin therapy and by 50% when used as a monotherapy.
• Evolocumab—a 47% to 71% reduction is achieved when evolocumab is added to a statin therapy and a 55% reduction when used as a monotherapy.
• Inclisiran—a 47% and 52% reduction in LDL-C levels is expected for inclisiran in combination with a statin therapy.
• Bempedoic acid—additional lowering of LDL-C when bempedoic acid alone is added to a background statin therapy is 12% to 16% and approximately 40% when bempedoic acid and ezetimibe are added to a background statin regimen.
• Adherence to LDL-C lowering diet—10% to <15% reduction is expected with good adherence to an LDL-C lowering diet.

Secondary Causes of Hyperlipidemia

Secondary causes of hyperlipidemia should be evaluated in selected patients with severe LDL-C (≥190 mg/dL), non– high-density lipoprotein cholesterol (HDL-C) (≥220 mg/dL) or triglyceride (≥500 mg/dL) elevations at baseline, or in patients whose LDL-C or triglyceride levels worsen despite adherence to drug and lifestyle therapy.

Common secondary causes of hypercholesterolemia include diet (saturated or transfats, weight gain, or anorexia), drugs (cyclosporine or glucocorticoids), diseases (biliary obstruction or nephrotic syndrome) and altered metabolism (hypothyroidism, obesity, or pregnancy). Untreated or uncontrolled diabetes is the most common cause of severe hypertriglyceridemia; other causes and their management are discussed in Managing Hypertriglyceridemia.

Treatment Intensification

Intensification of statin or lifestyle therapy, or the addition of a nonstatin LDL-C lowering drug, can be considered for additional LDL-C lowering in high-risk patients (clinical atherosclerotic cardiovascular disease (ASCVD) in patients ≤75 years of age or very high-risk ASCVD in patients of any age, or genetic hypercholesterolemia). Primary prevention patients with a 10-year ASCVD risk of 20% or higher might also be considered high risk. Addition of a nonstatin may be considered for selected high-risk patients with <50% reduction in LDL-C on maximally tolerated statin therapy, and with LDL-C ≥100 mg/dL, ≥70 mg/dL, or even ≥55 mg/dL (depending on the patient’s comorbidities and risk profile) on maximally tolerated statin therapy.

If a nonstatin is added, it should preferably be a nonstatin demonstrated to further reduce ASCVD risk when added to background statin therapy (ezetimibe or a PCSK9 monoclonal antibody).

Clinical Highlight I

• For patients with clinical ASCVD, LDL-C ≥190 mg/dL, or ≥20% 10-y ASCVD risk, at least a 50% reduction in LDL-C is desirable.
• Encourage adherence to healthy lifestyle habits and weight control.
• Maximize statin intensity as tolerated.
• Consider secondary causes of hyperlipidemia in patients who had been previously well-controlled.
• Consider adding ezetimibe in selected patients.
• May consider adding another nonstatin shown to reduce ASCVD events when added to background statin therapy in selected patients.

Maximize Statin Therapy

In patients unable to tolerate the recommended statin intensity, the maximum tolerated dose of statin should be used. Management of statin-associated side effects is discussed in the next section.